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BMC Cell Biology

Open Access

Connexinopathies: a structural and functional glimpse

  • Isaac E. García1,
  • Pavel Prado1,
  • Amaury Pupo1,
  • Oscar Jara1,
  • Diana Rojas-Gómez1,
  • Paula Mujica1,
  • Carolina Flores-Muñoz1,
  • Jorge González-Casanova1,
  • Carolina Soto-Riveros1,
  • Bernardo I. Pinto1,
  • Mauricio A. Retamal2,
  • Carlos González1 and
  • Agustín D. Martínez1Email author
Contributed equally
BMC Cell BiologyBMC series – open, inclusive and trusted201617(Suppl 1):S17

https://doi.org/10.1186/s12860-016-0092-x

Published: 24 May 2016

Abstract

Mutations in human connexin (Cx) genes have been related to diseases, which we termed connexinopathies. Such hereditary disorders include nonsyndromic or syndromic deafness (Cx26, Cx30), Charcot Marie Tooth disease (Cx32), occulodentodigital dysplasia and cardiopathies (Cx43), and cataracts (Cx46, Cx50). Despite the clinical phenotypes of connexinopathies have been well documented, their pathogenic molecular determinants remain elusive. The purpose of this work is to identify common/uncommon patterns in channels function among Cx mutations linked to human diseases. To this end, we compiled and discussed the effect of mutations associated to Cx26, Cx32, Cx43, and Cx50 over gap junction channels and hemichannels, highlighting the function of the structural channel domains in which mutations are located and their possible role affecting oligomerization, gating and perm/selectivity processes.

Keywords

Connexinshemichannelsgap junction channelsstructure and functionhuman genetic disease

Background

Connexin gap junction channels (GJCs) and hemichannels (HCs) are critical for cellular communication. GJCs allow the intercellular exchange of ions and small molecules (e.g., IP3, cAMP, cGMP, ATP) and diverse metabolites (e.g., sugars, amino acids, glutathione) (reviewed in [1]). The same molecules and ions can pass through HCs, but in this case to take part as autocrine and paracrine signals (reviewed by [2], [3]). Mutations in connexins (Cxs) genes are associated to genetic disorders such as skin abnormalities, cardiopathies, neurodegenerative and developmental diseases, cataracts, and most cases of hereditary deafness (reviewed by [4]–[6]).

Each HC is formed by the oligomerization of six Cxs subunits and the end-to-end docking of two HCs forms GJCs. The membrane topology of Cxs includes four transmembrane domains (designated as TM1-TM4) connected by two extracellular loops (ECL) and one intracellular loop (ICL). The amino terminus (NT) and the carboxyl terminus (CT) segments are cytoplasmic (Fig. 1a). Despite Cxs share high homology, there are important differences in the amino acid sequence of the ICL and CT. These segments contain motifs for regulatory kinases and cytoskeletal binding proteins [7], [8]. Oligomerization between suited isoforms also contributes to the assortment of Cx-based channels; for instances, heteromeric GJCs (HCs constituted by more than one Cxs type) and/or heterotypic channels (two homomeric HCs each made by a different Cxs type). These combinations may produce GJCs with particular functional and regulatory properties. Several works pointed out to TM3 in Cx32 [9]–[11] and Cx43 [12], and TM1 and NT segments in Cx26 [12], [13] as critical to regulate oligomerization of Cxs. In addition, a salt bridge between residues Glu-146 (TM3) and Arg-32 (TM1) in Cx32; and between Lys-22 (TM1) and Glu-209 (TM4) in Cx26, might sustain intraprotomer stability [14]. Nevertheless, the crystal structure of Cx26 showed that the main interactions between protomers occur at the extracellular side of the TM2 and TM4. Moreover, an aromatic cluster formed by the extracellular loops and TM3 also participates in inter-protomer interaction [15]. However, the oligomerization compatibility between Cxs has been associated to specific residues in the NT region [13], [16].
Fig. 1

Localization of loss-of-function mutations for Cx26 GJC. a Cartoon representation of a Cx26 monomer, colored with a blue-green gradient from the N- to the CT region. Localization of loss-of-function mutations are colored in red. b Lateral (c) Top (d) Bottom view of the same subunit of (a), in the context of the HC assemble. The HC surface is transparent and white. The figure was generated with PyMol and edited with Gimp

Cxs oligomerize to form a pore whose narrowest part is observed at the ECLs, near the docking zone [15], [17]. As mentioned above, the differences in the amino acid sequences among Cxs may influence the channel properties. It has been proposed that the membrane-spanning regions of Cxs are not only important for intra- and inter- protomer interactions, but they also might determine functional properties such as gating, permeability and the pore’s structure. Concerning the pore composition, there is some controversy about which TMs domains are involved. Some works pointed out the TM3 in Cx32 channels [11], [18] and TM1 in Cx46 channels [19], [20] as principal pore helix components. In support of the role of TM1 as a pore lining segment, it has been proposed that the voltage dependent loop-gating mechanism in the Cx32*Cx43 EL1 chimera (in which the ECL1 of Cx43 replaced the ECL1 of Cx32), involves a rotation of TM1 together with an inward tilt of the six protomers [21]. The 3.5 Å resolution of the Cx26 crystal structure revealed that TM1 is the main constituent of the pore [15] (Fig. 1). The structure also showed that the TM2 lines the pore but in a minor extent, whereas TM3 and TM4 face the hydrophobic membrane environment. The TM1 is tilted, which narrow the pore diameter to 14 Å from the cytoplasmic to the extracellular side of the membrane [15]. More recently, performing molecular dynamic refinements of the crystal structure of Cx26, Kwon and co-workers (2011) [22], shown that the narrow part of the pore could be even smaller.

As it was proposed previously for Cx32 [23] and then confirmed by Maeda and co-workers for Cx26 [15], the Cx-NT domain is located inside the pore, facing the TM1s and forming a funnel like structure that might restricts the pore diameter during gating process [15]. The intra-pore stabilization of the NT is achieved by hydrophobic interactions between residues Trp-3 (NT) and Met-34 (TM1) from neighboring protomers [15]. This interaction was previously proposed by Oshima and co-workers (2007), which found a prominent pore electron-density in the middle of the pore generated by the deafness mutant Cx26M34A. A reduction of this pore electron-density was observed when residues 2-7 (Cx26M34A-del2–7) were deleted [24], confirming the NT as major contributor to the pore occlusion.

Experiments using a chimeric HC of Cx32*Cx43ECL1, have provided more insight about the gating-mechanism of Cx-based channels [21]. In this chimera, the Cys substitution of the Ala residues in positions 40 and 43, located at the TM1/E1 border, form disulphide bonds with adjacent protomers when the cells are bathed in solutions expected to keep HCs closed (5 mM Ca2+or 10 µM Cd2+). These results strongly suggest a role for these residues in the “loop-gating” mechanism and extracellular Ca2+ regulation of HCs [21], [25].

GJCs and HCs gating regulation

How gating and permeability are regulated in Cxs- based channels is a matter of intense debate. To date, three types of gating mechanism have been proposed: 1) The NT as a voltage-sensor domain: that plugs the channel vestibule and contribute to the fast or V(j)-gating [15], [26], 2) The Loop gating: in which extracellular divalent cations (p.g., Ca2+) binds to the extracellular loops and blocks HCs by stabilizing the closed loop gate conformation [25], [27], and 3) The ball-and-chain model: which proposes that the CT as part of a ball-and-chain mechanism to regulate the gating of HCs. The last mechanism involves CT conformational rearrangements elicited by voltage or chemical (pH, redox, phosphorylation) stimuli, which promote a link between this segment and the ICL, and regulates the fast V(j)-gating mechanism [28]–[33]. This interaction requires the formation of alpha helical structures on the ICL peptide, in which the CT binds upon intracellular acidification [30].

Considering the relevance of the aforementioned mechanisms for channel function, it is critical to understand how Cxs mutations linked to diseases impair these processes. In the next sections, we describe genetic diseases associated to four Cxs that we used as models for the purpose of this review. For space reason, we did not include information about other important Cxs with mutations associated to disease, like Cx46 mutations linked to congenital cataracts [6], [34] or increased risk to developing diseases, like in polymorphisms in Cx37 genes associated to cardiovascular diseases [35].

Disease associated to Cx26 mutations

Genetic sensorineural hearing loss is associated mainly to mutations in Cx26 [36] (Table 1). Two clinical phenotypes derive from Cx26 mutations: 1) non-syndromic deafness, in which patients evince moderated to severe deafness with absence of other pathological manifestation; and 2) syndromic deafness, in which profound sensorineural hearing loss is accompanied by a range of severe tissue defects such as the observed in palmoplantar keratoderma [37], [38], keratitis ichthyosis deafness syndrome (KID) [39]–[42], Vohwinkel syndrome [43], histrix-like ichthyosis with deafness syndrome and Bart-Pumphrey syndrome [44], [45].
Table 1

Effect of mutations in Cx26 (GJB2) on the functional state of HCs and GJCs evaluated in a heterologous expression system, the domain that is affected and its phenotype

Domain

Mutation

GJCs Function

HCs Function

Deafness Phenotype

NT

M1V, T8M, G12V [13], [123], [132]–[136]

(−)

n.d.

NS, Profound, Moderate

G11E [130], [136], [137]

n.d.

(+)

S, Profound. KID

G12R(+*), N14K [13], [123], [136], [138]

(−)

(+)

S, Mild, Severe. KID/EKV

N14D [139]

n.d.

(−)

NS, Moderate

N14Y(+*) [13], [39], [136]

(−)

(+)

S, Profound. KID

S17F(+*) [13], [40], [123], [136]

(−)

(−)

S, SNHL. KID

TM1

V27I [140]

Normal

Normal

NS, HL and Normal

I33T [141]

(−)

n.d.

NS, Severe to Profound

M34T [36], [115], [142]–[146]

(−)

(−)

NS, Mild to Moderate; S, Profound. PPK

V37I, A40G [113], [143], [147]–[149]

(−)

(−)

NS, Mild-Moderate, Severe

A40V [124], [136], [150], [151]

Normal

(+)

S, Profound. KID

ECL1

DelE42, D66H [152]–[159]

(−)

n.d.

S, Profound, Moderate to Profound. PPK

W44C, W44S, D46E, T55N [142], [143], [152], [153], [159]–[163]

(−)

n.d.

NS, Severe to Profound, HL, Moderate, Severe

G45E [124], [130], [150], [164]–[166]

Normal

(+)

S, Profound. KID

E47K [164], [167]

(−)

(−)

NS, Severe to Profound

D50A [168], [169]

n.d.

(+)

S, Profound. KID

D50N [123], [137], [151], [170]–[172]

(−)

(+)

S, Profound. KID

G59V [144], [173]

n.d.

(−)

NS, Profound

R75Q, R75W [37], [134], [136], [141], [152]–[154], [174]

(−)

(−)

S, Severe to Profound. PPK

TM2

W77R, F83L, L90V, V95M [37], [135], [142], [143], [147], [173], [175], [176]

(−)

n.d.

NS, Moderate to Profound, Moderate, Profound

I82M [144], [177]

n.d.

(−)

NS, Profound

V84L [51], [147], [148], [178], [179]

Normal/No IP3 transfer

n.d

NS. Profound

T86R, A88S, L90P [132], [143], [144], [147], [160], [180]

(−)

(−)

NS, Profound, Moderate to Profound, Mild to Moderate

A88V [136], [168], [181]

n.d.

(+)

S, Severe to Profound. KID

ICL

E114G, R127H [115], [140], [144], [173], [178], [182], [183]

(−)

(−)

NS, Severe to Profound, Profound

DelE120 [141], [143], [147]

(−)

n.d.

NS, Severe to Profound

TM3

R143Q, R153I [133], [152], [153], [183], [184]

(−)

n.d.

NS, Profound

R143W [133], [144], [178], [185], [186]

(−)

(−)

NS, Profound

ECL2

F161S, P173R, D179N, R165W, W172R, R184P, R184Q [132], [141], [143], [147], [152], [153], [187]–[190]

(−)

n.d.

NS, HL, Severe to Profound, Profound

M163L [191]

n.d

(+)

NS, Moderate to Profound

S183F [136], [192]

(−)

n.d.

S, High Frequency HL. PPK

TM4

M195T, A197S,206S, L214P [133], [135], [190], [193], [194]

(−)

n.d.

NS, HL, Moderate, Profound

C202F [153], [193], [195]

n.d.

(−)

NS, Mild to Moderate

I203T, L205V [179], [193], [196]

(−)

(−)

NS, HL, Profound

NS Non-syndromic, S Syndromic, KID Keratitis-Ichthyosis-Deafness, EKV Erythrokeratodermia variabilis, PPK Palmoplantar Keratoderma-deafness, HL Hearing loss. (+*) = Generate gain of HC function when they are coexpressed with wild type Cx26 or Cx43 [13]

(−) = Loss of function. (+) = Gain of function. n.d. = not determined

Among the attempts to identify the pathogenic mechanism of KID syndrome, two transgenic animal models have been developed. They express the Cx26S17F and Cx26G45E mutations in the skin and/or cochlea [46], [47] and exhibit similar phenotypes than humans. Experimental results strongly support that the possible mechanisms in the skin might include the impairment of the epidermal calcium homeostasis and the disruption of the water barrier due to abnormal lipid composition of the stratum corneum [48]. For hearing loss, several hypotheses have been proposed. They include loss of Ca2+ homeostasis and ATP release [49], [50], impaired permeability to Ins(1,3,4) P3 [51], loss of the endocochlear potential by deficient K+ recycling between the epithelial GJ network and the stria vascularis [52], and developmental malformation or cochlear degeneration induced by massive cell death [53], [54]. For comprehensive reviews see [4], [55].

Disease associated to Cx32 mutations

Cx32 is expressed in several cell types, including the myelin-forming cells in both the peripheral and central nervous systems (CNS); the Schwann cells and oligodendrocytes, respectively. Mutations in this protein are associated to the most common X-linked inheritance form of the Charcot-Marie-Tooth disease (CMT), a pathology referred as CMT1X that accounts for the 10 % of all the CMT cases [56]–[58]. Due to its X-linkage, males display moderate to severe symptoms [59], [60], while milder phenotypes are observed in heterozygous females [61], [62].

In the peripheral nervous system, mutations in Cx32 induce progressive muscular atrophy and variable sensory loss, symptoms associated to slow axonal conduction and distal axonal loss [63]. However, prolonged central conductions times of sensory inputs also arise as consequence of Cx32 missense mutations [64]–[66].

Cx32 localizes in the axonal paranodes and Schmidt-Lantermann incisures [67]–[69] of the peripheral nerves. Hence, GJC made by this protein do not connect adjacent cells but contiguous loops of non-compact myelin. These channels likely act as a preferential diffusion pathway, significantly decreasing the distance between the nucleus and the adaxonal membrane of the myelin sheaths [67], [70].

The peripheral pathological mechanisms associated to Cx32 mutations possibly involve the loss of function of the GJC (Table 2), either by intracellular retention or the production of channels with aberrant properties [70]–[72]. This lack of functionality might reduce the transfer of signaling molecules, like cAMP, between the adaxonal portions and the nucleus of the Schwann cell [73].
Table 2

Effect of mutations in Cx32 (GJB1) on the functional state of HCs and GJCs evaluated in a heterologous expression system, the domain that is affected and its phenotype

Domain

Mutation

GJCs Function

HCs Function

CMTX Phenotype

NT

W3A, W3S, W3Y, G12S, W13L, V13L, R15W, R22G, R22X [127], [197]–[203]

(−)

n.d.

Mild to Severe, Severe, Mild to Moderate, Not described

TM1

S26L, M34K, A39V, A40V [70], [71], [204], [205]

(−)

n.d.

Mild, Not Described

M34T, V35M, V38M [70], [205], [206]

(−)

n.d.

Mild to Moderate, Severe

ECL1

G45E [207]

n.d.

(+)

Not Described

ECL1

C53S, C60F, Y65C, R75P [203], [205], [208]–[210]

(−)

n.d.

Not Described

T55I, R75Q, R75W [72], [204], [205], [209], [210],

(−)

n.d.

Mild

TM2

S85C [127], [211]

n.d.

(+)

Severe, Mild

T86A, T86S, T86N, T87A [70], [212]

(−)

(−)

Not Described, Mild

H94Y, H94Q [127], [206]

(−)

n.d.

Mild to Moderate

M93V, V95M [203], [204], [206]

(−)

n.d.

Not Described, Mild to Moderate

ICL

E102G, Null111-116 [71], [198], [202], [213]

(−)

n.d.

Mild, Mild to Moderate

R107W, R129H [203], [214]

(−)

n.d.

Mild to Moderate, Not described

TM3

V139M, V140E, R142W [127], [197], [209], [215]–[219]

(−)

n.d.

Mild to Moderate, Mild to Severe, Moderate to Severe

ECL2

L143P, L156R [203], [218]

(−)

n.d.

Mild to Moderate

R164Q, V181A, E186K [197], [204], [206], [213], [214], [216], [219]

(−)

n.d.

Moderate to Severe

R164W, P172R, S182T, R183H [72], [198], [203], [204], [206], [208]

(−)

n.d.

Mild to Moderate, Not Described

TM4

G199R, R203C, N205I [203], [205], [206], [214]

(−)

n.d.

Moderate to Severe, Not Described

E208K, R208K [197], [202], [203], [216], [220], [221]

(−)

(−)

Moderate to Severe

Y211X [203], [222]

(−)

n.d.

Severe

CT

R215W [206], [209], [221]

(−)

(−)

Mild to Moderate

C217X [198], [220]

n.d.

(−)

Severe

R220X [71], [197], [198], [206], [220]

(−)

n.d.

Moderate to Severe

F235C [126]

n.d.

(+)

Severe

R265X [198]

(−)

(−)

Severe

(−) = Loss of function. (+) = Gain of function. n.d. = not determined

Furthermore, at least some effects of Cx32 mutations have been associated to a gain of function of the GJC (Table 2). Nevertheless, this is based on indirect electrophysiological studies performed in two patients who do not express Cx32; these patients display visual and auditory evoked responses with normal central conduction times [74], [75]. However, the absence of central functional disruptions in most CMT1X patients and Cx32-KO animals supports the hypothesis of gain of function of GJC in patients where disease also affects CNS [61], [76], [77]. However, further studies about the functional properties of the Cx32 channels are required to support these hypothesis.

Disease associated to Cx43 mutations

Oculodentodigital Dysplasia (ODDD) is the most important human disease related to Cx43 mutations (Table 3). ODDD is a autosomal inherited developmental disorder affecting face, eyes, teeth and limbs (reviewed in [1], [78]). This pathology was linked to a germ line Cx43 gene (GJA1) mutation [79]. The phenotype varies from syndactyli type III alone, to ODDD without syndactyli [80], [81], camptodactyli [79], cardiac impairments, mild cognitive retardation [82] and skeletal abnormalities, which could be associated to impaired osteoblast differentiation [83].
Table 3

Effect of mutations in Cx43 (GJA1) on the functional state of HCs and GJCs evaluated in a heterologous expression system, the domain that is affected and its phenotype

Domain

Mutant

GJCs Function

HCs Function

Phenotype

NT

G2V, D3N, W4A, L7V, L11P, S18P [79], [92], [223]–[225]

(−)

n.d.

ODDD

G12R, Y17S [79], [90], [92], [223], [226]–[228]

(−)

(−)

ODDD

TM1

I31M [91], [229]

(−)

(+)

ODDD

R33X [81], [230]

(−)

n.d.

Small deep-set eyes, syndactyli, dental abnormalities

ECL1

A40V, L90V, F52dup [79], [226], [227], [229], [231]

(−)

(−)

ODDD

E42K [232], [233]

(−)

n.d.

Sudden infant death, lethal ventricular arrhythmias

Q49K [79], [227], [231], [234]

(−)

n.d.

ODDD

S69P [235]

(−)

n.d.

Nonsyndromic Hearing Loss

R76H [230], [236]

(−)

n.d.

Hallermann-Streiff syndrome: small stature, hypotrichosis, teeth and skeletal abnormalities

ICL

I130T [79], [89], [226], [227]

(−)

(−)

ODDD

K134E, T154A [89], [226], [236]–[239]

(−)

n.d.

ODDD

G138R, G143S [79], [89]–[92]

(−)

(+)

ODDD

H194P [80], [91]

(−)

Normal

ODDD

ECL2

R202H, V216L [79], [92], [226], [228], [229], [231]

(−)

n.d.

ODDD

TM4

Fs230, Fs260 [92], [240]

(−)

n.d.

ODDD

S272P [232]

Normal

n.d.

Sudden infant death

CT

T326I [235]

(−)

n.d.

Nonsyndromic Hearing Loss

S364P [98], [241]

(−)

n.d.

Viscero-atrial heterotaxia/heart malformations

(−) = Loss of function. (+) = Gain of function. n.d. = not determined

Currently, over 74 mutations related with ODDD have been reported. However, less than a half of these mutations have been characterized. Missense mutations of Cx43 associated to ODDD are spread through Cx43 amino acid sequence without a clear pattern (Table 3). However, most mutations concentrate in the first half of the protein, with few localized at the CT region (Table 3). The CT domain has several residues that may be phosphorylated, and these allow the regulation of processes like communication, trafficking to the plasma membrane and assembly and degradation of the gap junction protein [84]. The CT also interacts with the ZO-1 [85], v-Scr [86] and other proteins, including cytoskeletal proteins [87].

Several mutations associated to ODDD are located in the ICL region of Cx43 (Table 3), demonstrating the importance of this domain for Cx43 based channels functionality. ICL is critical for both, the pH-mediated gating and the architecture of the channel pore [88]. For example, the ODDD mutant Cx43G138R, which is located in this domain, results in unfunctional GJCs when expressed in N2A cells [89]–[92]. In contrast, the mutation increases the HC activity determined by ATP release measurements [91]. Moreover, a mouse model carrying this mutation (Cx43G138R) exhibits a phenotype that resembled the observed in humans, i.e., craniofacial alterations, bilateral syndactyli, smaller teeth (microdontia), unspecialized enamel hypoplasia, osteopenia and sparse hair [93].

A principal role of Cx43 GJCs in the myocardium is to allow a rapid and coordinated electrical excitation important for the cardiac-action potential propagation. Cx43 is mainly located at the intercalated discs in the ventricular myocardium. The geometrical arrangement of the discs, as well as the total number of GJCs, seems to be determinant for the characteristic anisotropic conduction of the ventricular myocardium. The atrial myocardium expresses high levels of Cx43 and Cx40 in addition to small quantities of Cx45 [94]. In addition, it has been reported that cells forming the conduction system (responsible for rapid electrical signal localization from the sinoatrial node to the ventricles), express Cx43, Cx45, Cx40, and Cx30 [95], [96]. However, patients with mutation in Cx43 rarely exhibit cardiac problems (Table 3). In addition, congenital heart diseases are not commonly associated to Cx43 mutations [97]. Until now, only a few cases of Cx43 mutations linked to heart diseases have been reported. For example Ser364Pro, which results in viscera atrial heterotaxia [98] restrict GJCs communication in transfected cells. A subsequent work of Thibodeau et al. [99] showed a frameshift mutation in a patient with atrial fibrillation. This modification involves a single nucleotide deletion (c.932delC) with 36 aberrant amino acids with a consecutive stop codon. Interestingly, the mutation was absent in peripheral blood lymphocytes and the immunohistological analysis from left atrial tissue showed areas with normal GJCs localization but at the same time, areas with predominant intracellular retention of Cx.

Disease associated to Cx50 mutations

Fibers and epithelial cells in the eye lens are connected through Cx50 GJCs [100]–[102]. This communication is required to maintain the ionic conditions necessary to avoid the formation of cataract [103], a pathology resulting in the opacity of the lens, restricting the amount of light reaching the retina. The Cx50 mutations (Table 4) have been identified in members of families with inherited cataracts. The phenotype may vary across patients, in which missense locations and frame shifts have been commonly identified (reviewed in [6]).
Table 4

Effect of mutations in Cx50 (GJA8) on the functional state of HCs and GJCs evaluated in a heterologous expression system, the domain that is affected and its phenotype

Domain

Mutation

GJCs Function

HCs Function

Cataract Phenotype

NT

R23T [242]

(−)

n.d.

Bilateral nuclear

TM1/ECL1

V44A [243]

n.d

(−)

Suture-sparing nuclear

V44E [110]

(−)

n.d.

Whole lens

W45S [106], [244]

(−)

(−)

Jellyfish-like appearance, Micro cornea

ECL1

G46V [104], [106]

(+)

(+)

Total

D47N [110], [117]

(−)

n.d.

Nuclear Pulverulent

E48K [116], [245]

(−)

Normal

Zonular Nuclear Pulverulent

S50P [114], [118]

(−)

(−)

Altered fiber cell formation, dense cataract and posterior capsule rupture

TM2

V79L [110]

(−)

n.d.

“Full moon” with Y-suture Opacities

P88S [34], [246]

(−)

n.d.

Zonular Pulverulent

P88Q [247]

(−)

n.d.

Lamellar Pulverulent

CT

S276F [248], [249]

(−)

(−)

Nuclear Pulverulent

Cx50fs [250]

(−)

n.d.

Triangular

(−) = Loss of function. (+) = Gain of function. n.d. = not determined

All Cx50 mutations produce loss of function GJCs, except G46V that produce gain of function GJCs [104]. These mutations could generate both, mislocalization and impaired function of GJCs and HCs (e.g., gating or charge selectivity) [105]–[107]. At cellular level, it is possible that Cx50 mutations affect the intercellular communication mediated by heteromeric Cx46-Cx50 GJCs. This idea is based on results demonstrating that these Cxs co-localize at GJCs plaques [108]–[110]. The defective GJCs activity could alter the solute transport between cells and disrupt the Ca2+ homeostasis [111], [112]. The abnormal ion transport, especially Na+ ions, causes lens swelling and ameliorates the fluid circulation inside the structure. These abnormal processes might affect the nutrient transport and the clearance of noxious metabolites, triggering the cataract formation [112].

Location of mutations associated to diseases and their functional consequences on GJC and HCs

Taking advantage of the natural occurring mutations in Cxs and previous studies focuses in the effect of disease-associated mutations on the functional state of GJCs and HCs, we looked for similarities and differences between Cxs regarding the positions of mutations associated to the respective diseases and its functional consequences on GJCs and HCs.

Tables summarize experimental results on GJCs and HCs obtained for different Cxs and disease conditions. They show that independent of the disease and Cx, all mutations produce loss of function of the GJCs, which can be partial or total. The decreased GJCs activity can be consequence of reduced amount of channels in the appositional membranes or changes in the functional properties of single channels.

It has been well established that a loss of function of the GJCs elicited by Cx mutations is sufficient to develop pathology. However, it is not clear if the extent of the loss of function is related to the severity of the disease. An institutive reasoning is that there is a good positive correlation between the severity of the Cx-linked disease and the loss of function of the corresponding GJCs. Unfortunately, the experimental data do not support this statement. On one side, positive correlation can be found when the analysis is restricted to some missense non-syndromic Cx26 mutations (V37I and A40G). While these genetic modifications induce GJCs with loss of function (A40G) and active channels with reduced permeability (V37I) [113], they produce a severe deafness phenotype and a milder condition, respectively [4]. However, a clear correlation cannot be established when other mutations are analyzed, such as some Cx32 mutations associated to a mild to moderate (Null111-116) and moderate to severe (R220X) CMTX1 phenotypes. As expected, the permeability of these channels to different dye tracers decreases as the size of the probe increases [114]. However, unlike the channels containing the Null111-116 mutation, permeability of the R220X-Cx32 GJCs to small probes (neurobiotin) is not significantly different from that observed in wild type channels [115]. In the same region (TM1-ECL1) other mutations cause nonfunctional GJCs and HCs (eg. E48K, D47N, S50P) [110], [116]–[118]. In contrast, Cx50 W45S acts as a dominant negative when co-expressed with Cx50, reducing GJCs coupling between fibers cells [106]. The above evidences suggest that the disease mechanisms might be produced by subtle changes in GJCs permeability, which are impossible to detect by the common electrophysiological and dye coupling methodologies.

In order to know the location of mutations in the channel structure, we produced several molecular models of the different Cxs by homology modeling, taking the crystal structure of Cx26 GJC published by Maeda et al., (2009) as template [15]. Due to the lack of experimental structure for human Cx32, Cx43 and Cx50, we generated comparative structural models, using Modeller [119], based on the structure of human Cx26 as a template (pdb: 2ZW3) (Figs. 2 and 3). Missing residues of human Cx26 structure were inserted with Modeller. The backbone of the experimental Cx26 structure was fully conserved. Ten models were generated in each case and those with the lowest discrete optimized protein energy (DOPE) score were selected as the final models. Figure 1 shows the model of a Cx26 monomer in the context of the connexon as well the location of residues mutated in genetic deafness that produce loss of function GJCs. Clearly, although loss of function mutations can be located everywhere in the protomer, they are concentrated from the NT to the TM2 domains (Fig. 1), regions that line the pore and are critical for voltage gating, as we mentioned earlier [120]. Moreover, other mutations in the transmembrane regions seem to be located in protein-protein and protein-lipid interfaces (Fig. 1b, c). Those locations could be important for intra- or inter-protomer interactions [121], which might stabilize the channel or contribute GJCs channel assembly. For Cx32, the pattern for location of mutations that produced loss of function GJCs is very similar to that observed for Cx26 (Fig. 2b), suggesting strong similarities in the structural features between these two Cxs. For Cxs 43 and 50, mutations that produce loss of GJCs function are more restricted. The fact that they localize mostly from NT to ECL1 (Fig. 2c, d) confirms the importance of this region for the channel function in the whole Cx family. However, the ICL Cx43 also presents important amount of mutations producing loss of function GJCs (Table 3).
Fig. 2

Mutations affecting function of GJCs. Models of single Cxs chains are represented as cartoons, and colored with a blue-green gradient from the N- to the CT region, for (a) Cx26 (b) Cx32, (c) Cx43 and (d) Cx50. Positions of loss of function mutations are colored as red and gain of function mutations as yellow. The figure was generated with Pymol and edited with Gimp

Fig. 3

Mutations affecting function of HCs. Models of single Cxs chains are represented as cartoons, and colored with a blue-green gradient from the N- to the CT region, for (a) Cx26 (b) Cx32, (c) Cx43 and (d) Cx50. Positions of loss of function mutations are colored as red and gain of function mutations as yellow. The figure was generated with PyMol and edited with Gimp

Mutations affecting HCs function

The HCs play important role in physiological and pathological conditions since they provide a route for paracrine/autocrine signaling between the cell and the extracellular environment [2], [122]. Hence, a plausible underlying mechanism for connexinopathies is the possibility that some disease condition arise upon HCs dysfunction. For example, aberrant gain of function HCs is associated to syndromic Cx26 mutations that lead to keratitis ichthyosis deafness syndrome (KID) [13], [123], [124]. For the other Cxs (Cx32, Cx43 and Cx50), very few cases have been reported making it difficult to establish a common mechanism of disease (Tables 1, 2, 3 and 4). Exceptions are some mutations in Cx32 (S85C and F235C), which induce aberrant gain of HC activity in CMTX1 [125], [126], which behaves similar to the KID-linked Cx26 mutations, i.e., causing a gain of function of the HCs [125] and a loss of function of the GJCs [127]. Although the S85C mutant induces abnormal HCs opening [128], this mutation has not been associated to any particular severe phenotype of CMTX1 [129].

Most of the mutations eliciting gain of HCs function are clustered exclusively in the pore lining residues of the NT, TM1 and the ECL1. They also localize in TM2 to a lesser extent (Fig. 3). In the case of Cx26, several mutations related to severe clinical phenotypes of KID are located at the transition zone between TM1 and the ECL1, a domain involved in both voltage gating and the control of HCs by extracellular Ca2+ [25]. Moreover, a cluster of syndromic mutations is found in the NT domain of the protein, which is involved in the fast gating of HCs [24], [130]. Nevertheless, a role of other regions on the regulation of HCs should be further considered. For example, the Cx32 mutation F235C, localized in the CT of the protein also induces HCs with gain of function [126].

The gain of HCs function has been also observed in Cx43 related connexinopathies, since mutations I31M (TM1), G138R (ICL) and G143S (ICL), all promotes gain of function (Table 3). As mentioned above, ICL is involved in regulation the fast V(j)-gating, which depend on the interaction with CT [28]–[32]. Moreover, Dobrowolski and co-workers (2008) [93] found an increased ATP-release in cultured cardiomyocytes from cardiac specific G138R-mutant mice. Interestingly, the authors proposed that HCs with gain of function in G138R-mutated cardiomyocytes might be one of the causes of arrhythmias.

As expected, some mutations induce loss of function HCs (Table 1 and Fig. 3). For example, mutations related to non-syndromic sensorineural hearing loss generate non-functional HCs [113]. Indeed, there are some syndromic mutations that exhibit non-functional HCs that only become gain of function when are co-expressed with their wild type partner or under aberrant interaction with Cx43 [13], [131].

Finally, It should be considering that in normal tissues cells could express several Cxs isoforms raising the possibility of interaction among Cxs isoforms. Recent results obtained in Dr. Martinez’ lab [13] and Dr. White’s group [131] suggest that the interaction between the mutated Cx and the co-expressed Cxs forming heterotypic/heteromeric channels needs to be taking into account to explain the clinical phenotypes of connexinopathies. Thus, interaction of mutants with wild type Cxs might ameliorate or worsen the clinical phenotypes. This possibility might augment when mutations affect critical segment involved in oligomerization compatibility, giving rise to aberrant heteromeric HCs, which makes pathological condition and effective treatment complex. In this scenario, further studies attempting to explore the pathological mechanism of connexinopathies should consider to study Cxs in heteromeric rather than homomeric states, which more closely resembles native cellular conditions.

Conclusions

Most mutations causing connexinopathies generates total or partial loss of GJCs function. However, it is unclear if the severity of disease correlates with the level of GJCs loss of function. Mutations associated with loss of function GJCs are distributed along the entire protein sequence with no clear pattern of clustering at any segment, which suggest that GJC functionality is very sensitive to minor changes in Cxs protein, and that subtle changes in GJC functionality are sufficient to cause diseases. Less in known about the effect of mutations associated to connexinopathies on the functional state of HCs. The clearest correlation between gain of function HCs and disease has been found in most types of syndromic deafness associated to Cx26, in particular in KID syndrome. For others Cxs, few mutations are associated to gain of HCs function, however, we can not discard that this condition may be underestimated because most studies in the past have been more focused in GJCs than HCs. Therefore, it is yet difficult to make a general statement that represent all Cxs associated to connexinopathies. Nevertheless, it is clear that all mutations eliciting gain of HCs function are clustered in pore-associated domains like the NT and the TM1/ECL1, which are critical regions for gating and regulation.

Notes

Declarations

Acknowledgements

This work was supported by Anillo #ACT 1104 (to ADM, CG and MAR), Fondecyt #1130855 (to ADM) and #1120214 (to MAR), and Fondecyt Postdoctoral #3150634 (to IEG) and #3150442 (to PP). The Centro Interdisciplinario de Neurociencias de Valparaíso is a Chilean Millennium Institute (P09-022-F).

Declarations

Publication charge for this article was funded by grant Fondecyt #1130855 (to ADM).

This article has been published as part of BMC Cell Biology Volume 17 Supplement 1, 2016: Proceedings of the International Gap Junction Conference 2015. The full contents of the supplement are available online at http://bmccellbiol.biomedcentral.com/articles/supplements/volume-17-supplement-1.

Authors’ Affiliations

(1)
Centro Interdisciplinario de Neurociencia de Valparaíso, Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valparaíso
(2)
Centro de Fisiología Celular e Integrativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo

References

  1. Laird DW: Syndromic and non-syndromic disease-linked Cx43 mutations. FEBS Lett. 2014, 588 (8): 1339-1348.PubMedGoogle Scholar
  2. Sáez JC, Berthoud VM, Branes MC, Martínez AD, Beyer EC: Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev. 2003, 83 (4): 1359-1400.PubMedGoogle Scholar
  3. Harris AL: Emerging issues of connexin channels: biophysics fills the gap. Q Rev Biophys. 2001, 34 (3): 325-472.PubMedGoogle Scholar
  4. Martínez AD, Acuña R, Figueroa V, Maripillán J, Nicholson B: Gap-junction channels dysfunction in deafness and hearing loss. Antioxid Redox Signal. 2009, 11 (2): 309-322.PubMedPubMed CentralGoogle Scholar
  5. Delmar M, Makita N: Cardiac connexins, mutations and arrhythmias. Curr Opin Cardiol. 2012, 27 (3): 236-241.PubMedGoogle Scholar
  6. Beyer EC, Ebihara L, Berthoud VM: Connexin mutants and cataracts. Front Pharmacol. 2013, 4: 43PubMedPubMed CentralGoogle Scholar
  7. Laird DW, Castillo M, Kasprzak L: Gap junction turnover, intracellular trafficking, and phosphorylation of connexin43 in brefeldin A-treated rat mammary tumor cells. J Cell Biol. 1995, 131 (5): 1193-1203.PubMedGoogle Scholar
  8. Lampe PD, Lau AF: Regulation of gap junctions by phosphorylation of connexins. Arch Biochem Biophys. 2000, 384 (2): 205-215.PubMedGoogle Scholar
  9. Ahmad S, Martin PE, Evans WH: Assembly of gap junction channels: mechanism, effects of calmodulin antagonists and identification of connexin oligomerization determinants. Eur J Biochem. 2001, 268 (16): 4544-4552.PubMedGoogle Scholar
  10. Maza J, Das Sarma J, Koval M: Defining a minimal motif required to prevent connexin oligomerization in the endoplasmic reticulum. J Biol Chem. 2005, 280 (22): 21115-21121.PubMedGoogle Scholar
  11. Fleishman SJ, Unger VM, Yeager M, Ben-Tal N: A Calpha model for the transmembrane alpha helices of gap junction intercellular channels. Mol Cell. 2004, 15 (6): 879-888.PubMedGoogle Scholar
  12. Martinez AD, Maripillan J, Acuna R, Minogue PJ, Berthoud VM, Beyer EC: Different domains are critical for oligomerization compatibility of different connexins. Biochem J. 2011, 436 (1): 35-43.PubMedPubMed CentralGoogle Scholar
  13. García IE, Maripillán J, Jara O, Ceriani R, Palacios-Muñoz A, Ramachandran J, Olivero P, Perez-Acle T, González C, Sáez JC, et al: Keratitis-Ichthyosis-Deafness Syndrome-Associated Cx26 Mutants Produce Nonfunctional Gap Junctions but Hyperactive Hemichannels When Co-Expressed With Wild Type Cx43. J Invest Dermatol. 2015, 135 (5): 1338-1347.PubMedPubMed CentralGoogle Scholar
  14. Fleishman SJ, Sabag AD, Ophir E, Avraham KB, Ben-Tal N: The structural context of disease-causing mutations in gap junctions. J Biol Chem. 2006, 281 (39): 28958-28963.PubMedGoogle Scholar
  15. Maeda S, Nakagawa S, Suga M, Yamashita E, Oshima A, Fujiyoshi Y, Tsukihara T: Structure of the connexin 26 gap junction channel at 3.5 A resolution. Nature. 2009, 458 (7238): 597-602.PubMedGoogle Scholar
  16. Lagree V, Brunschwig K, Lopez P, Gilula NB, Richard G, Falk MM: Specific amino-acid residues in the N-terminus and TM3 implicated in channel function and oligomerization compatibility of connexin43. J Cell Sci. 2003, 116 (Pt 15): 3189-3201.PubMedGoogle Scholar
  17. Unger VM, Kumar NM, Gilula NB, Yeager M: Three-dimensional structure of a recombinant gap junction membrane channel. Science. 1999, 283 (5405): 1176-1180.PubMedGoogle Scholar
  18. Skerrett IM, Aronowitz J, Shin JH, Cymes G, Kasperek E, Cao FL, Nicholson BJ: Identification of amino acid residues lining the pore of a gap junction channel. J Cell Biol. 2002, 159 (2): 349-360.PubMedPubMed CentralGoogle Scholar
  19. Zhou XW, Pfahnl A, Werner R, Hudder A, Llanes A, Luebke A, Dahl G: Identification of a pore lining segment in gap junction hemichannels. Biophys J. 1997, 72 (5): 1946-1953.PubMedPubMed CentralGoogle Scholar
  20. Kronengold J, Trexler EB, Bukauskas FF, Bargiello TA, Verselis VK: Single-channel SCAM identifies pore-lining residues in the first extracellular loop and first transmembrane domains of Cx46 hemichannels. J Gen Physiol. 2003, 122 (4): 389-405.PubMedPubMed CentralGoogle Scholar
  21. Tang Q, Dowd TL, Verselis VK, Bargiello TA: Conformational changes in a pore-forming region underlie voltage-dependent “loop gating” of an unapposed connexin hemichannel. J Gen Physiol. 2009, 133 (6): 555-570.PubMedPubMed CentralGoogle Scholar
  22. Kwon T, Harris AL, Rossi A, Bargiello TA: Molecular dynamics simulations of the Cx26 hemichannel: evaluation of structural models with Brownian dynamics. J Gen Physiol. 2011, 138 (5): 475-493.PubMedPubMed CentralGoogle Scholar
  23. Purnick PE, Benjamin DC, Verselis VK, Bargiello TA, Dowd TL: Structure of the amino terminus of a gap junction protein. Arch Biochem Biophys. 2000, 381 (2): 181-190.PubMedGoogle Scholar
  24. Oshima A, Tani K, Hiroaki Y, Fujiyoshi Y, Sosinsky GE: Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule. Proc Natl Acad Sci U S A. 2007, 104 (24): 10034-10039.PubMedPubMed CentralGoogle Scholar
  25. Verselis VK, Srinivas M: Divalent cations regulate connexin hemichannels by modulating intrinsic voltage-dependent gating. J Gen Physiol. 2008, 132 (3): 315-327.PubMedPubMed CentralGoogle Scholar
  26. Oh S, Bargiello TA: Voltage regulation of connexin channel conductance. Yonsei Med J. 2015, 56 (1): 1-15.PubMedGoogle Scholar
  27. Gomez-Hernandez JM, de Miguel M, Larrosa B, Gonzalez D, Barrio LC: Molecular basis of calcium regulation in connexin-32 hemichannels. Proc Natl Acad Sci U S A. 2003, 100 (26): 16030-16035.PubMedPubMed CentralGoogle Scholar
  28. Solan JL, Lampe PD: Connexin43 phosphorylation: structural changes and biological effects. Biochem J. 2009, 419 (2): 261-272.PubMedPubMed CentralGoogle Scholar
  29. Spray DC, Burt JM: Structure-activity relations of the cardiac gap junction channel. Am J Phys. 1990, 258 (2 Pt 1): C195-C205.Google Scholar
  30. Hirst-Jensen BJ, Sahoo P, Kieken F, Delmar M, Sorgen PL: Characterization of the pH-dependent interaction between the gap junction protein connexin43 carboxyl terminus and cytoplasmic loop domains. J Biol Chem. 2007, 282 (8): 5801-5813.PubMedGoogle Scholar
  31. Elenes S, Martinez AD, Delmar M, Beyer EC, Moreno AP: Heterotypic docking of Cx43 and Cx45 connexons blocks fast voltage gating of Cx43. Biophys J. 2001, 81 (3): 1406-1418.PubMedPubMed CentralGoogle Scholar
  32. Revilla A, Castro C, Barrio LC: Molecular dissection of transjunctional voltage dependence in the connexin-32 and connexin-43 junctions. Biophys J. 1999, 77 (3): 1374-1383.PubMedPubMed CentralGoogle Scholar
  33. Duffy HS, Sorgen PL, Girvin ME, O'Donnell P, Coombs W, Taffet SM, Delmar M, Spray DC. pH-dependent intramolecular binding and structure involving Cx43 cytoplasmic domains. J Biol Chem. 2002;277(39):36706–14.PubMedGoogle Scholar
  34. Berthoud VM, Minogue PJ, Guo J, Williamson EK, Xu X, Ebihara L, Beyer EC: Loss of function and impaired degradation of a cataract-associated mutant connexin50. Eur J Cell Biol. 2003, 82 (5): 209-221.PubMedPubMed CentralGoogle Scholar
  35. Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, Sone T, Tanaka M, Yokota M: Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002, 347 (24): 1916-1923.PubMedGoogle Scholar
  36. Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM: Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997, 387 (6628): 80-83.PubMedGoogle Scholar
  37. Richard G, White TW, Smith LE, Bailey RA, Compton JG, Paul DL, Bale SJ: Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. Hum Genet. 1998, 103 (4): 393-399.PubMedGoogle Scholar
  38. Heathcote K, Syrris P, Carter ND, Patton MA: A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350). J Med Genet. 2000, 37 (1): 50-51.PubMedPubMed CentralGoogle Scholar
  39. Arita K, Akiyama M, Aizawa T, Umetsu Y, Segawa I, Goto M, Sawamura D, Demura M, Kawano K, Shimizu H: A novel N14Y mutation in Connexin26 in keratitis-ichthyosis-deafness syndrome: analyses of altered gap junctional communication and molecular structure of N terminus of mutated Connexin26. Am J Pathol. 2006, 169 (2): 416-423.PubMedPubMed CentralGoogle Scholar
  40. Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynanen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, et al: Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet. 2002, 70 (5): 1341-1348.PubMedPubMed CentralGoogle Scholar
  41. Mazereeuw-Hautier J, Bitoun E, Chevrant-Breton J, Man SY, Bodemer C, Prins C, Antille C, Saurat JH, Atherton D, Harper JI, et al: Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients. Br J Dermatol. 2007, 156 (5): 1015-1019.PubMedGoogle Scholar
  42. van Steensel MA, van Geel M, Nahuys M, Smitt JH, Steijlen PM: A novel connexin 26 mutation in a patient diagnosed with keratitis-ichthyosis-deafness syndrome. J Invest Dermatol. 2002, 118 (4): 724-727.PubMedGoogle Scholar
  43. Maestrini E, Korge BP, Ocana-Sierra J, Calzolari E, Cambiaghi S, Scudder PM, Hovnanian A, Monaco AP, Munro CS: A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) in three unrelated families. Hum Mol Genet. 1999, 8 (7): 1237-1243.PubMedGoogle Scholar
  44. van Geel M, van Steensel MA, Kuster W, Hennies HC, Happle R, Steijlen PM, Konig A: HID and KID syndromes are associated with the same connexin 26 mutation. Br J Dermatol. 2002, 146 (6): 938-942.PubMedGoogle Scholar
  45. Alexandrino F, Sartorato EL, Marques-de-Faria AP, Steiner CE: G59S mutation in the GJB2 (connexin 26) gene in a patient with Bart-Pumphrey syndrome. Am J Med Genet A. 2005, 136 (3): 282-284.PubMedGoogle Scholar
  46. Schütz M, Auth T, Gehrt A, Bosen F, Korber I, Strenzke N, Moser T, Willecke K: The connexin26 S17F mouse mutant represents a model for the human hereditary keratitis-ichthyosis-deafness syndrome. Hum Mol Genet. 2011, 20 (1): 28-39.PubMedGoogle Scholar
  47. Mese G, Sellitto C, Li L, Wang HZ, Valiunas V, Richard G, Brink PR, White TW: The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome. Mol Biol Cell. 2011, 22 (24): 4776-4786.PubMedPubMed CentralGoogle Scholar
  48. Bosen F, Celli A, Crumrine D, Vom Dorp K, Ebel P, Jastrow H, Dormann P, Winterhager E, Mauro T, Willecke K: Altered epidermal lipid processing and calcium distribution in the KID syndrome mouse model Cx26S17F. FEBS Lett. 2015, 589 (15): 1904-1910.PubMedPubMed CentralGoogle Scholar
  49. Zhao HB: Connexin26 is responsible for anionic molecule permeability in the cochlea for intercellular signalling and metabolic communications. Eur J Neurosci. 2005, 21 (7): 1859-1868.PubMedPubMed CentralGoogle Scholar
  50. Mammano F: Ca2+ homeostasis defects and hereditary hearing loss. Biofactors. 2011, 37 (3): 182-188.PubMedGoogle Scholar
  51. Beltramello M, Piazza V, Bukauskas FF, Pozzan T, Mammano F: Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol. 2005, 7 (1): 63-69.PubMedGoogle Scholar
  52. Zhao HB, Kikuchi T, Ngezahayo A, White TW: Gap junctions and cochlear homeostasis. J Membr Biol. 2006, 209 (2–3): 177-186.PubMedPubMed CentralGoogle Scholar
  53. Cohen-Salmon M, Ott T, Michel V, Hardelin JP, Perfettini I, Eybalin M, Wu T, Marcus DC, Wangemann P, Willecke K, et al: Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr Biol: CB. 2002, 12 (13): 1106-1111.PubMedPubMed CentralGoogle Scholar
  54. Kammen-Jolly K, Ichiki H, Scholtz AW, Gsenger M, Kreczy A, Schrott-Fischer A: Connexin 26 in human fetal development of the inner ear. Hear Res. 2001, 160 (1–2): 15-21.PubMedGoogle Scholar
  55. Wingard JC, Zhao HB: Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss - A Common Hereditary Deafness. Front Cell Neurosci. 2015, 9: 202PubMedPubMed CentralGoogle Scholar
  56. Kleopa KA, Abrams CK, Scherer SS: How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease?. Brain Res. 2012, 1487: 198-205.PubMedPubMed CentralGoogle Scholar
  57. Murphy SM, Ovens R, Polke J, Siskind CE, Laura M, Bull K, Ramdharry G, Houlden H, Murphy RP, Shy ME, et al: X inactivation in females with X-linked Charcot-Marie-Tooth disease. Neuromuscul Disord. 2012, 22 (7): 617-621.PubMedPubMed CentralGoogle Scholar
  58. Saporta MA, Shy ME: Inherited peripheral neuropathies. Neurol Clin. 2013, 31 (2): 597-619.PubMedPubMed CentralGoogle Scholar
  59. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME: Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011, 69 (1): 22-33.PubMedPubMed CentralGoogle Scholar
  60. Latour P, Gonnaud PM, Ollagnon E, Chan V, Perelman S, Stojkovic T, Stoll C, Vial C, Ziegler F, Vandenberghe A, et al: SIMPLE mutation analysis in dominant demyelinating Charcot-Marie-Tooth disease: three novel mutations. J Peripher Nerv Syst. 2006, 11 (2): 148-155.PubMedGoogle Scholar
  61. Scherer SS, Xu YT, Nelles E, Fischbeck K, Willecke K, Bone LJ: Connexin32-null mice develop demyelinating peripheral neuropathy. Glia. 1998, 24 (1): 8-20.PubMedGoogle Scholar
  62. Siskind CE, Shy ME: Genetics of neuropathies. Semin Neurol. 2011, 31 (5): 494-505.PubMedGoogle Scholar
  63. Abrams CK, Scherer SS: Gap junctions in inherited human disorders of the central nervous system. Biochim Biophys Acta. 2012, 1818 (8): 2030-2047.PubMedGoogle Scholar
  64. Nicholson G, Corbett A: Slowing of central conduction in X-linked Charcot-Marie-Tooth neuropathy shown by brain stem auditory evoked responses. J Neurol Neurosurg Psychiatry. 1996, 61 (1): 43-46.PubMedPubMed CentralGoogle Scholar
  65. Srinivasan J, Leventer RJ, Kornberg AJ, Dahl HH, Ryan MM: Central nervous system signs in X-linked Charcot-Marie-Tooth disease after hyperventilation. Pediatr Neurol. 2008, 38 (4): 293-295.PubMedGoogle Scholar
  66. Kassubek J, Bretschneider V, Sperfeld AD: Corticospinal tract MRI hyperintensity in X-linked Charcot-Marie-Tooth Disease. J Clin Neurosci. 2005, 12 (5): 588-589.PubMedGoogle Scholar
  67. Scherer SS, Deschenes SM, Xu YT, Grinspan JB, Fischbeck KH, Paul DL: Connexin32 is a myelin-related protein in the PNS and CNS. J Neurosci. 1995, 15 (12): 8281-8294.PubMedGoogle Scholar
  68. Altevogt BM, Kleopa KA, Postma FR, Scherer SS, Paul DL: Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems. J Neurosci. 2002, 22 (15): 6458-6470.PubMedGoogle Scholar
  69. Balice-Gordon RJ, Bone LJ, Scherer SS: Functional gap junctions in the schwann cell myelin sheath. J Cell Biol. 1998, 142 (4): 1095-1104.PubMedPubMed CentralGoogle Scholar
  70. Oh S, Ri Y, Bennett MV, Trexler EB, Verselis VK, Bargiello TA: Changes in permeability caused by connexin 32 mutations underlie X-linked Charcot-Marie-Tooth disease. Neuron. 1997, 19 (4): 927-938.PubMedGoogle Scholar
  71. Bicego M, Morassutto S, Hernandez VH, Morgutti M, Mammano F, D'Andrea P, Bruzzone R. Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease. Neurobiol Dis. 2006;21(3):607–17.PubMedGoogle Scholar
  72. Sargiannidou I, Vavlitou N, Aristodemou S, Hadjisavvas A, Kyriacou K, Scherer SS, Kleopa KA: Connexin32 mutations cause loss of function in Schwann cells and oligodendrocytes leading to PNS and CNS myelination defects. J Neurosci. 2009, 29 (15): 4736-4749.PubMedPubMed CentralGoogle Scholar
  73. Ressot C, Bruzzone R: Connexin channels in Schwann cells and the development of the X-linked form of Charcot-Marie-Tooth disease. Brain Res Brain Res Rev. 2000, 32 (1): 192-202.PubMedGoogle Scholar
  74. Takashima H, Nakagawa M, Umehara F, Hirata K, Suehara M, Mayumi H, Yoshishige K, Matsuyama W, Saito M, Jonosono M, et al: Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease. Acta Neurol Scand. 2003, 107 (1): 31-37.PubMedGoogle Scholar
  75. Hahn AF, Ainsworth PJ, Bolton CF, Bilbao JM, Vallat JM: Pathological findings in the x-linked form of Charcot-Marie-Tooth disease: a morphometric and ultrastructural analysis. Acta Neuropathol. 2001, 101 (2): 129-139.PubMedGoogle Scholar
  76. Anzini P, Neuberg DH, Schachner M, Nelles E, Willecke K, Zielasek J, Toyka KV, Suter U, Martini R: Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32. J Neurosci. 1997, 17 (12): 4545-4551.PubMedGoogle Scholar
  77. Sutor B, Schmolke C, Teubner B, Schirmer C, Willecke K: Myelination defects and neuronal hyperexcitability in the neocortex of connexin 32-deficient mice. Cereb Cortex. 2000, 10 (7): 684-697.PubMedGoogle Scholar
  78. Molica F, Meens MJ, Morel S, Kwak BR: Mutations in cardiovascular connexin genes. Biol Cell. 2014, 106 (9): 269-293.PubMedGoogle Scholar
  79. Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, et al: Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet. 2003, 72 (2): 408-418.PubMedGoogle Scholar
  80. Vitiello C, D’Adamo P, Gentile F, Vingolo EM, Gasparini P, Banfi S: A novel GJA1 mutation causes oculodentodigital dysplasia without syndactyly. Am J Med Genet A. 2005, 133A (1): 58-60.PubMedGoogle Scholar
  81. Richardson RJ, Joss S, Tomkin S, Ahmed M, Sheridan E, Dixon MJ: A nonsense mutation in the first transmembrane domain of connexin 43 underlies autosomal recessive oculodentodigital syndrome. J Med Genet. 2006, 43 (7): e37PubMedPubMed CentralGoogle Scholar
  82. Loddenkemper T, Grote K, Evers S, Oelerich M, Stogbauer F: Neurological manifestations of the oculodentodigital dysplasia syndrome. J Neurol. 2002, 249 (5): 584-595.PubMedGoogle Scholar
  83. McLachlan E, Plante I, Shao Q, Tong D, Kidder GM, Bernier SM, Laird DW: ODDD-linked Cx43 mutants reduce endogenous Cx43 expression and function in osteoblasts and inhibit late stage differentiation. J Bone Miner Res. 2008, 23 (6): 928-938.PubMedGoogle Scholar
  84. Laird DW: Connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation. Biochim Biophys Acta. 2005, 1711 (2): 172-182.PubMedGoogle Scholar
  85. Giepmans BN, Verlaan I, Moolenaar WH: Connexin-43 interactions with ZO-1 and alpha- and beta-tubulin. Cell Commun Adhes. 2001, 8 (4–6): 219-223.PubMedGoogle Scholar
  86. Kanemitsu MY, Loo LW, Simon S, Lau AF, Eckhart W: Tyrosine phosphorylation of connexin 43 by v-Src is mediated by SH2 and SH3 domain interactions. J Biol Chem. 1997, 272 (36): 22824-22831.PubMedGoogle Scholar
  87. Giepmans BN: Gap junctions and connexin-interacting proteins. Cardiovasc Res. 2004, 62 (2): 233-245.PubMedGoogle Scholar
  88. Delmar M, Coombs W, Sorgen P, Duffy HS, Taffet SM: Structural bases for the chemical regulation of Connexin43 channels. Cardiovasc Res. 2004, 62 (2): 268-275.PubMedGoogle Scholar
  89. Seki A, Coombs W, Taffet SM, Delmar M: Loss of electrical communication, but not plaque formation, after mutations in the cytoplasmic loop of connexin43. Heart Rhythm. 2004, 1 (2): 227-233.PubMedGoogle Scholar
  90. Roscoe W, Veitch GI, Gong XQ, Pellegrino E, Bai D, McLachlan E, Shao Q, Kidder GM, Laird DW: Oculodentodigital dysplasia-causing connexin43 mutants are non-functional and exhibit dominant effects on wild-type connexin43. J Biol Chem. 2005, 280 (12): 11458-11466.PubMedGoogle Scholar
  91. Dobrowolski R, Sommershof A, Willecke K: Some oculodentodigital dysplasia-associated Cx43 mutations cause increased hemichannel activity in addition to deficient gap junction channels. J Membr Biol. 2007, 219 (1–3): 9-17.PubMedGoogle Scholar
  92. Churko JM, Langlois S, Pan X, Shao Q, Laird DW: The potency of the fs260 connexin43 mutant to impair keratinocyte differentiation is distinct from other disease-linked connexin43 mutants. Biochem J. 2010, 429 (3): 473-483.PubMedPubMed CentralGoogle Scholar
  93. Dobrowolski R, Sasse P, Schrickel JW, Watkins M, Kim JS, Rackauskas M, Troatz C, Ghanem A, Tiemann K, Degen J, et al: The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans. Hum Mol Genet. 2008, 17 (4): 539-554.PubMedGoogle Scholar
  94. Severs NJ, Bruce AF, Dupont E, Rothery S: Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res. 2008, 80 (1): 9-19.PubMedPubMed CentralGoogle Scholar
  95. Garcia-Dorado D, Rodriguez-Sinovas A, Ruiz-Meana M: Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovasc Res. 2004, 61 (3): 386-401.PubMedGoogle Scholar
  96. van Kempen MJ, ten Velde I, Wessels A, Oosthoek PW, Gros D, Jongsma HJ, Moorman AF, Lamers WH: Differential connexin distribution accommodates cardiac function in different species. Microsc Res Tech. 1995, 31 (5): 420-436.PubMedGoogle Scholar
  97. Huang GY, Xie LJ, Linask KL, Zhang C, Zhao XQ, Yang Y, Zhou GM, Wu YJ, Marquez-Rosado L, McElhinney DB, et al: Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models. J Cardiovasc Dis Res. 2011, 2 (4): 206-212.PubMedPubMed CentralGoogle Scholar
  98. Britz-Cunningham SH, Shah MM, Zuppan CW, Fletcher WH: Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality. N Engl J Med. 1995, 332 (20): 1323-1329.PubMedGoogle Scholar
  99. Thibodeau IL, Xu J, Li Q, Liu G, Lam K, Veinot JP, Birnie DH, Jones DL, Krahn AD, Lemery R, et al: Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. Circulation. 2010, 122 (3): 236-244.PubMedGoogle Scholar
  100. TenBroek EM, Johnson R, Louis CF: Cell-to-cell communication in a differentiating ovine lens culture system. Invest Ophthalmol Vis Sci. 1994, 35 (1): 215-228.PubMedGoogle Scholar
  101. Dahm R: Lens fibre cell differentiation - A link with apoptosis?. Ophthalmic Res. 1999, 31 (3): 163-183.PubMedGoogle Scholar
  102. Rong P, Wang X, Niesman I, Wu Y, Benedetti LE, Dunia I, Levy E, Gong X: Disruption of Gja8 (alpha8 connexin) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation. Development. 2002, 129 (1): 167-174.PubMedGoogle Scholar
  103. White TW, Bruzzone R, Goodenough DA, Paul DL: Mouse Cx50, a functional member of the connexin family of gap junction proteins, is the lens fiber protein MP70. Mol Biol Cell. 1992, 3 (7): 711-720.PubMedPubMed CentralGoogle Scholar
  104. Minogue PJ, Tong JJ, Arora A, Russell-Eggitt I, Hunt DM, Moore AT, Ebihara L, Beyer EC, Berthoud VM: A mutant connexin50 with enhanced hemichannel function leads to cell death. Invest Ophthalmol Vis Sci. 2009, 50 (12): 5837-5845.PubMedPubMed CentralGoogle Scholar
  105. Xu X, Berthoud VM, Beyer EC, Ebihara L: Functional role of the carboxyl terminal domain of human connexin 50 in gap junctional channels. J Membr Biol. 2002, 186 (2): 101-112.PubMedPubMed CentralGoogle Scholar
  106. Tong JJ, Minogue PJ, Guo W, Chen TL, Beyer EC, Berthoud VM, Ebihara L: Different consequences of cataract-associated mutations at adjacent positions in the first extracellular boundary of connexin50. Am J Physiol Cell Physiol. 2011, 300 (5): C1055-C1064.PubMedPubMed CentralGoogle Scholar
  107. Beyer EC, Berthoud VM: Connexin hemichannels in the lens. Front Physiol. 2014, 5: 20PubMedPubMed CentralGoogle Scholar
  108. Paul DL, Ebihara L, Takemoto LJ, Swenson KI, Goodenough DA: Connexin46, a novel lens gap junction protein, induces voltage-gated currents in nonjunctional plasma membrane of Xenopus oocytes. J Cell Biol. 1991, 115 (4): 1077-1089.PubMedGoogle Scholar
  109. Jiang JX, Goodenough DA: Heteromeric connexons in lens gap junction channels. Proc Natl Acad Sci U S A. 1996, 93 (3): 1287-1291.PubMedPubMed CentralGoogle Scholar
  110. Rubinos C, Villone K, Mhaske PV, White TW, Srinivas M: Functional effects of Cx50 mutations associated with congenital cataracts. Am J Physiol Cell Physiol. 2014, 306 (3): C212-C220.PubMedGoogle Scholar
  111. Gao J, Sun X, Martinez-Wittinghan FJ, Gong X, White TW, Mathias RT: Connections between connexins, calcium, and cataracts in the lens. J Gen Physiol. 2004, 124 (4): 289-300.PubMedPubMed CentralGoogle Scholar
  112. Mathias RT, White TW, Gong X: Lens gap junctions in growth, differentiation, and homeostasis. Physiol Rev. 2010, 90 (1): 179-206.PubMedPubMed CentralGoogle Scholar
  113. Jara O, Acuna R, Garcia IE, Maripillan J, Figueroa V, Saez JC, Araya-Secchi R, Lagos CF, Perez-Acle T, Berthoud VM, et al: Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function. Mol Biol Cell. 2012, 23 (17): 3299-3311.PubMedPubMed CentralGoogle Scholar
  114. DeRosa AM, Xia CH, Gong X, White TW: The cataract-inducing S50P mutation in Cx50 dominantly alters the channel gating of wild-type lens connexins. J Cell Sci. 2007, 120 (Pt 23): 4107-4116.PubMedGoogle Scholar
  115. Bicego M, Beltramello M, Melchionda S, Carella M, Piazza V, Zelante L, Bukauskas FF, Arslan E, Cama E, Pantano S, et al: Pathogenetic role of the deafness-related M34T mutation of Cx26. Hum Mol Genet. 2006, 15 (17): 2569-2587.PubMedPubMed CentralGoogle Scholar
  116. Banks EA, Toloue MM, Shi Q, Zhou ZJ, Liu J, Nicholson BJ, Jiang JX: Connexin mutation that causes dominant congenital cataracts inhibits gap junctions, but not hemichannels, in a dominant negative manner. J Cell Sci. 2009, 122 (Pt 3): 378-388.PubMedPubMed CentralGoogle Scholar
  117. Arora A, Minogue PJ, Liu X, Addison PK, Russel-Eggitt I, Webster AR, Hunt DM, Ebihara L, Beyer EC, Berthoud VM, et al: A novel connexin50 mutation associated with congenital nuclear pulverulent cataracts. J Med Genet. 2008, 45 (3): 155-160.PubMedGoogle Scholar
  118. DeRosa AM, Mese G, Li L, Sellitto C, Brink PR, Gong X, White TW: The cataract causing Cx50-S50P mutant inhibits Cx43 and intercellular communication in the lens epithelium. Exp Cell Res. 2009, 315 (6): 1063-1075.PubMedPubMed CentralGoogle Scholar
  119. Sali A, Blundell TL: Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993, 234 (3): 779-815.PubMedGoogle Scholar
  120. Bargiello TA, Tang Q, Oh S, Kwon T: Voltage-dependent conformational changes in connexin channels. Biochim Biophys Acta. 2012, 1818 (8): 1807-1822.PubMedGoogle Scholar
  121. Fleishman SJ, Ben-Tal N: Progress in structure prediction of alpha-helical membrane proteins. Curr Opin Struct Biol. 2006, 16 (4): 496-504.PubMedGoogle Scholar
  122. Retamal MA, Reyes EP, Garcia IE, Pinto B, Martinez AD, Gonzalez C: Diseases associated with leaky hemichannels. Front Cell Neurosci. 2015, 9: 267PubMedPubMed CentralGoogle Scholar
  123. Lee JR, Derosa AM, White TW: Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes. J Invest Dermatol. 2009, 129 (4): 870-878.PubMedGoogle Scholar
  124. Gerido DA, DeRosa AM, Richard G, White TW: Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness. Am J Physiol Cell Physiol. 2007, 293 (1): C337-C345.PubMedGoogle Scholar
  125. Abrams CK, Bennett MV, Verselis VK, Bargiello TA: Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease. Proc Natl Acad Sci U S A. 2002, 99 (6): 3980-3984.PubMedPubMed CentralGoogle Scholar
  126. Liang GS, de Miguel M, Gomez-Hernandez JM, Glass JD, Scherer SS, Mintz M, et al. Severe neuropathy with leaky connexin32 hemichannels. Ann Neurol. 2005;57(5):749–54.PubMedGoogle Scholar
  127. Abrams CK, Freidin MM, Verselis VK, Bennett MV, Bargiello TA: Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res. 2001, 900 (1): 9-25.PubMedPubMed CentralGoogle Scholar
  128. Abrams CK, Oh S, Ri Y, Bargiello TA: Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot-Marie-Tooth disease. Brain Res Brain Res Rev. 2000, 32 (1): 203-214.PubMedGoogle Scholar
  129. Kleopa KA, Sargiannidou I: Connexins, gap junctions and peripheral neuropathy. Neurosci Lett. 2015, 596: 27-32.PubMedGoogle Scholar
  130. Sánchez HA, Verselis VK: Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss. Front Cell Neurosci. 2014, 8: 354PubMedPubMed CentralGoogle Scholar
  131. Shuja Z, Li L, Gupta S, Mese G, White TW. Connexin26 Mutations Causing Palmoplantar Keratoderma and Deafness Interact with connexin43, Modifying Gap Junction and Hemichannel Properties. J Invest Dermatol. 2016;136(1):225-35. doi:10.1038/JID.2015.389.PubMedPubMed CentralGoogle Scholar
  132. Thonnissen E, Rabionet R, Arbones ML, Estivill X, Willecke K, Ott T: Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002, 111 (2): 190-197.PubMedGoogle Scholar
  133. Mese G, Londin E, Mui R, Brink PR, White TW: Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. Hum Genet. 2004, 115 (3): 191-199.PubMedGoogle Scholar
  134. Chen Y, Deng Y, Bao X, Reuss L, Altenberg GA: Mechanism of the defect in gap-junctional communication by expression of a connexin 26 mutant associated with dominant deafness. FASEB J. 2005, 19 (11): 1516-1518.PubMedGoogle Scholar
  135. Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, et al: Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002, 4 (4): 279-288.PubMedGoogle Scholar
  136. Iossa S, Marciano E, Franze A: GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss. Curr Genomics. 2011, 12 (7): 475-785.PubMedPubMed CentralGoogle Scholar
  137. Terrinoni A, Codispoti A, Serra V, Didona B, Bruno E, Nistico R, Giustizieri M, Alessandrini M, Campione E, Melino G: Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation. Biochem Biophys Res Commun. 2010, 394 (4): 909-914.PubMedGoogle Scholar
  138. de Zwart-Storm EA, Rosa RF, Martin PE, Foelster-Holst R, Frank J, Bau AE, Zen PR, Graziadio C, Paskulin GA, Kamps MA, et al: Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes. Exp Dermatol. 2011, 20 (5): 408-412.PubMedGoogle Scholar
  139. Haack B, Schmalisch K, Palmada M, Bohmer C, Kohlschmidt N, Keilmann A, Zechner U, Limberger A, Beckert S, Zenner HP, et al: Deficient membrane integration of the novel p. N14D-GJB2 mutant associated with non-syndromic hearing impairment. Hum Mutat. 2006, 27 (11): 1158-1159.PubMedGoogle Scholar
  140. Choi SY, Lee KY, Kim HJ, Kim HK, Chang Q, Park HJ, Jeon CJ, Lin X, Bok J, Kim UK: Functional evaluation of GJB2 variants in nonsyndromic hearing loss. Mol Med. 2011, 17 (5–6): 550-556.PubMedPubMed CentralGoogle Scholar
  141. Mani RS, Ganapathy A, Jalvi R, Srikumari Srisailapathy CR, Malhotra V, Chadha S, Agarwal A, Ramesh A, Rangasayee RR, Anand A: Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. Eur J Hum Genet: EJHG. 2009, 17 (4): 502-509.PubMedGoogle Scholar
  142. Martin PE, Coleman SL, Casalotti SO, Forge A, Evans WH: Properties of connexin26 gap junctional proteins derived from mutations associated with non-syndromal heriditary deafness. Hum Mol Genet. 1999, 8 (13): 2369-2376.PubMedGoogle Scholar
  143. Zhang Y, Tang W, Ahmad S, Sipp JA, Chen P, Lin X: Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions. Proc Natl Acad Sci U S A. 2005, 102 (42): 15201-15206.PubMedPubMed CentralGoogle Scholar
  144. Palmada M, Schmalisch K, Bohmer C, Schug N, Pfister M, Lang F, Blin N: Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006, 22 (1): 112-118.PubMedGoogle Scholar
  145. Skerrett IM, Di WL, Kasperek EM, Kelsell DP, Nicholson BJ: Aberrant gating, but a normal expression pattern, underlies the recessive phenotype of the deafness mutant Connexin26M34T. FASEB J. 2004, 18 (7): 860-862.PubMedGoogle Scholar
  146. White TW, Deans MR, Kelsell DP, Paul DL: Connexin mutations in deafness. Nature. 1998, 394 (6694): 630-631.PubMedGoogle Scholar
  147. Bruzzone R, Veronesi V, Gomes D, Bicego M, Duval N, Marlin S, Petit C, D'Andrea P, White TW. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003;533(1–3):79–88.PubMedGoogle Scholar
  148. Kenna MA, Wu BL, Cotanche DA, Korf BR, Rehm HL: Connexin 26 studies in patients with sensorineural hearing loss. Arch otolaryngol--head & neck Surg. 2001, 127 (9): 1037-1042.Google Scholar
  149. Kim J, Jung J, Lee MG, Choi JY, Lee KA: Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene. Exp Mol Med. 2015, 47: e169PubMedPubMed CentralGoogle Scholar
  150. Sánchez HA, Mese G, Srinivas M, White TW, Verselis VK: Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome. J Gen Physiol. 2010, 136 (1): 47-62.PubMedPubMed CentralGoogle Scholar
  151. Sánchez HA, Bienkowski R, Slavi N, Srinivas M, Verselis VK: Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome. J Biol Chem. 2014, 289 (31): 21519-21532.PubMedPubMed CentralGoogle Scholar
  152. Zhang J, Scherer SS, Yum SW: Dominant Cx26 mutants associated with hearing loss have dominant-negative effects on wild type Cx26. Mol Cell Neurosci. 2011, 47 (2): 71-78.PubMedGoogle Scholar
  153. Yum SW, Zhang J, Scherer SS: Dominant connexin26 mutants associated with human hearing loss have trans-dominant effects on connexin30. Neurobiol Dis. 2010, 38 (2): 226-236.PubMedPubMed CentralGoogle Scholar
  154. Marziano NK, Casalotti SO, Portelli AE, Becker DL, Forge A: Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Hum Mol Genet. 2003, 12 (8): 805-812.PubMedGoogle Scholar
  155. Bakirtzis G, Choudhry R, Aasen T, Shore L, Brown K, Bryson S, Forrow S, Tetley L, Finbow M, Greenhalgh D, et al: Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. Hum Mol Genet. 2003, 12 (14): 1737-1744.PubMedGoogle Scholar
  156. Thomas T, Jordan K, Simek J, Shao Q, Jedeszko C, Walton P, Laird DW: Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration. J Cell Sci. 2005, 118 (Pt 19): 4451-4462.PubMedGoogle Scholar
  157. Thomas T, Telford D, Laird DW: Functional domain mapping and selective trans-dominant effects exhibited by Cx26 disease-causing mutations. J Biol Chem. 2004, 279 (18): 19157-19168.PubMedGoogle Scholar
  158. Thomas T, Aasen T, Hodgins M, Laird DW: Transport and function of cx26 mutants involved in skin and deafness disorders. Cell Commun Adhes. 2003, 10 (4–6): 353-358.PubMedGoogle Scholar
  159. Rouan F, White TW, Brown N, Taylor AM, Lucke TW, Paul DL, Munro CS, Uitto J, Hodgins MB, Richard G: Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. J Cell Sci. 2001, 114 (Pt 11): 2105-2113.PubMedGoogle Scholar
  160. Choi SY, Park HJ, Lee KY, Dinh EH, Chang Q, Ahmad S, Lee SH, Bok J, Lin X, Kim UK: Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss. Hum Mutat. 2009, 30 (7): E716-E727.PubMedGoogle Scholar
  161. Bruzzone R, Gomes D, Denoyelle E, Duval N, Perea J, Veronesi V, Weil D, Petit C, Gabellec MM, D'Andrea P, et al. Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness. Cell Commun Adhes. 2001;8(4–6):425–31.PubMedGoogle Scholar
  162. Melchionda S, Bicego M, Marciano E, Franze A, Morgutti M, Bortone G, Zelante L, Carella M, D'Andrea P. Functional characterization of a novel Cx26 (T55N) mutation associated to non-syndromic hearing loss. Biochem Biophys Res Commun. 2005;337(3):799–805.PubMedGoogle Scholar
  163. Tekin M, Arnos KS, Xia XJ, Oelrich MK, Liu XZ, Nance WE, Pandya A: W44C mutation in the connexin 26 gene associated with dominant non-syndromic deafness. Clin Genet. 2001, 59 (4): 269-273.PubMedGoogle Scholar
  164. Stong BC, Chang Q, Ahmad S, Lin X: A novel mechanism for connexin 26 mutation linked deafness: cell death caused by leaky gap junction hemichannels. Laryngoscope. 2006, 116 (12): 2205-2210.PubMedGoogle Scholar
  165. Ogawa Y, Takeichi T, Kono M, Hamajima N, Yamamoto T, Sugiura K, Akiyama M: Revertant mutation releases confined lethal mutation, opening Pandora’s box: a novel genetic pathogenesis. PLoS Genet. 2014, 10 (5): e1004276PubMedPubMed CentralGoogle Scholar
  166. Oguchi T, Ohtsuka A, Hashimoto S, Oshima A, Abe S, Kobayashi Y, Nagai K, Matsunaga T, Iwasaki S, Nakagawa T, et al: Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns. J Hum Genet. 2005, 50 (2): 76-83.PubMedGoogle Scholar
  167. Prasad S, Cucci RA, Green GE, Smith RJ: Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000, 16 (6): 502-508.PubMedGoogle Scholar
  168. Mhaske PV, Levit NA, Li L, Wang HZ, Lee JR, Shuja Z, Brink PR, White TW: The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. Am J Physiol Cell Physiol. 2013, 304 (12): C1150-C1158.PubMedPubMed CentralGoogle Scholar
  169. Cushing SL, MacDonald L, Propst EJ, Sharma A, Stockley T, Blaser SL, James AL, Papsin BC: Successful cochlear implantation in a child with Keratosis, Icthiosis and Deafness (KID) Syndrome and Dandy-Walker malformation. Int J Pediatr Otorhinolaryngol. 2008, 72 (5): 693-698.PubMedGoogle Scholar
  170. Lopez W, Gonzalez J, Liu Y, Harris AL, Contreras JE: Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N/Y). J Gen Physiol. 2013, 142 (1): 23-35.PubMedPubMed CentralGoogle Scholar
  171. Terrinoni A, Codispoti A, Serra V, Bruno E, Didona B, Paradisi M, Nistico S, Campione E, Napolitano B, Diluvio L, et al: Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss. Biochem Biophys Res Commun. 2010, 395 (1): 25-30.PubMedGoogle Scholar
  172. Sánchez HA, Villone K, Srinivas M, Verselis VK: The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions. J Gen Physiol. 2013, 142 (1): 3-22.PubMedPubMed CentralGoogle Scholar
  173. Toth T, Kupka S, Haack B, Riemann K, Braun S, Fazakas F, Zenner HP, Muszbek L, Blin N, Pfister M, et al: GJB2 mutations in patients with non-syndromic hearing loss from Northeastern Hungary. Hum Mutat. 2004, 23 (6): 631-632.PubMedGoogle Scholar
  174. Piazza V, Beltramello M, Menniti M, Colao E, Malatesta P, Argento R, Chiarella G, Gallo LV, Catalano M, Perrotti N, et al: Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss. Clin Genet. 2005, 68 (2): 161-166.PubMedGoogle Scholar
  175. Bajaj Y, Sirimanna T, Albert DM, Qadir P, Jenkins L, Bitner-Glindzicz M: Spectrum of GJB2 mutations causing deafness in the British Bangladeshi population. Clin Otolaryngol. 2008, 33 (4): 313-318.PubMedGoogle Scholar
  176. Carrasquillo MM, Zlotogora J, Barges S, Chakravarti A: Two different connexin 26 mutations in an inbred kindred segregating non–syndromic recessive deafness: implications for genetic studies in isolated populations. Hum Mol Genet. 1997, 6 (12): 2163-2172.PubMedGoogle Scholar
  177. Kupka S, Braun S, Aberle S, Haack B, Ebauer M, Zeissler U, Zenner HP, Blin N, Pfister M: Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non–syndromic hearing impairment. Hum Mutat. 2002, 20 (1): 77-78.PubMedGoogle Scholar
  178. Wang HL, Chang WT, Li AH, Yeh TH, Wu CY, Chen MS, Huang PC: Functional analysis of connexin–26 mutants associated with hereditary recessive deafness. J Neurochem. 2003, 84 (4): 735-742.PubMedGoogle Scholar
  179. Ambrosi C, Boassa D, Pranskevich J, Smock A, Oshima A, Xu J, Nicholson BJ, Sosinsky GE: Analysis of four connexin26 mutant gap junctions and hemichannels reveals variations in hexamer stability. Biophys J. 2010, 98 (9): 1809-1819.PubMedPubMed CentralGoogle Scholar
  180. Cryns K, Orzan E, Murgia A, Huygen PL, Moreno F, del Castillo I, Chamberlin GP, Azaiez H, Prasad S, Cucci RA, et al: A genotype–phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet. 2004, 41 (3): 147-154.PubMedPubMed CentralGoogle Scholar
  181. Meigh L, Hussain N, Mulkey DK, Dale N: Connexin26 hemichannels with a mutation that causes KID syndrome in humans lack sensitivity to CO2. Elife. 2014, 3: e04249PubMedPubMed CentralGoogle Scholar
  182. Posukh O, Pallares–Ruiz N, Tadinova V, Osipova L, Claustres M, Roux AF: First molecular screening of deafness in the Altai Republic population. BMC Med Genet. 2005, 6: 12PubMedPubMed CentralGoogle Scholar
  183. Loffler J, Nekahm D, Hirst-Stadlmann A, Gunther B, Menzel HJ, Utermann G, Janecke AR. Sensorineural hearing loss and the incidence of Cx26 mutations in Austria. Eur J Hum Genet. 2001;9(3):226–30.PubMedGoogle Scholar
  184. Marlin S, Garabedian EN, Roger G, Moatti L, Matha N, Lewin P, Petit C, Denoyelle F: Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. Arch Otolaryngol Head Neck Surg. 2001, 127 (8): 927-933.PubMedGoogle Scholar
  185. Man YK, Trolove C, Tattersall D, Thomas AC, Papakonstantinopoulou A, Patel D, et al. A deafness–associated mutant human connexin 26 improves the epithelial barrier in vitro. J Membr Biol. 2007;218(1–3):29–37.PubMedPubMed CentralGoogle Scholar
  186. Brobby GW, Muller–Myhsok B, Horstmann RD: Connexin 26 R143W mutation associated with recessive nonsyndromic sensorineural deafness in Africa. N Engl J Med. 1998, 338 (8): 548-550.PubMedGoogle Scholar
  187. Xiao Z, Yang Z, Liu X, Xie D: Impaired membrane targeting and aberrant cellular localization of human Cx26 mutants associated with inherited recessive hearing loss. Acta Otolaryngol. 2011, 131 (1): 59-66.PubMedGoogle Scholar
  188. Rickard S, Kelsell DP, Sirimana T, Rajput K, MacArdle B, Bitner–Glindzicz M: Recurrent mutations in the deafness gene GJB2 (connexin 26) in British Asian families. J Med Genet. 2001, 38 (8): 530-533.PubMedPubMed CentralGoogle Scholar
  189. Denoyelle F, Weil D, Maw MA, Wilcox SA, Lench NJ, Allen-Powell DR, Osborn AH, Dahl HH, Middleton A, Houseman MJ, et al. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet. 1997;6(12):2173–7.PubMedGoogle Scholar
  190. Hamelmann C, Amedofu GK, Albrecht K, Muntau B, Gelhaus A, Brobby GW, Horstmann RD: Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. Hum Mutat. 2001, 18 (1): 84-85.PubMedGoogle Scholar
  191. Matos TD, Caria H, Simoes-Teixeira H, Aasen T, Dias O, Andrea M, Kelsell DP, Fialho G. A novel M163L mutation in connexin 26 causing cell death and associated with autosomal dominant hearing loss. Hear Res. 2008;240(1–2):87–92.PubMedGoogle Scholar
  192. de Zwart–Storm EA, van Geel M, van Neer PA, Steijlen PM, Martin PE, van Steensel MA: A novel missense mutation in the second extracellular domain of GJB2, p. Ser183Phe, causes a syndrome of focal palmoplantar keratoderma with deafness. Am J Pathol. 2008, 173 (4): 1113-1119.PubMedPubMed CentralGoogle Scholar
  193. Ambrosi C, Walker AE, Depriest AD, Cone AC, Lu C, Badger J, Skerrett IM, Sosinsky GE: Analysis of trafficking, stability and function of human connexin 26 gap junction channels with deafness–causing mutations in the fourth transmembrane helix. PLoS One. 2013, 8 (8): e70916PubMedPubMed CentralGoogle Scholar
  194. Mese G, Valiunas V, Brink PR, White TW: Connexin26 deafness associated mutations show altered permeability to large cationic molecules. Am J Physiol Cell Physiol. 2008, 295 (4): C966-C974.PubMedPubMed CentralGoogle Scholar
  195. Morle L, Bozon M, Alloisio N, Latour P, Vandenberghe A, Plauchu H, Collet L, Edery P, Godet J, Lina-Granade G. A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss. J Med Genet. 2000;37(5):368–70.PubMedPubMed CentralGoogle Scholar
  196. Yilmaz A, Menevse S, Bayazit Y, Karamert R, Ergin V, Menevse A: Two novel missense mutations in the connexin 26 gene in Turkish patients with nonsyndromic hearing loss. Biochem Genet. 2010, 48 (3–4): 248-256.PubMedGoogle Scholar
  197. Deschenes SM, Walcott JL, Wexler TL, Scherer SS, Fischbeck KH: Altered trafficking of mutant connexin32. J neurosci: J Soc Neurosci. 1997, 17 (23): 9077-9084.Google Scholar
  198. Ionasescu V, Ionasescu R, Searby C: Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy. Am J Med Genet. 1996, 63 (3): 486-491.PubMedGoogle Scholar
  199. Fryns JP, Van den Berghe H: Sex-linked recessive inheritance in Charcot-Marie-tooth disease with partial clinical manifestations in female carriers. Hum Genet. 1980, 55 (3): 413-415.PubMedGoogle Scholar
  200. Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, Garcia CA: Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease. Muscle Nerve. 2000, 23 (2): 182-188.PubMedGoogle Scholar
  201. Senderek J, Hermanns B, Bergmann C, Boroojerdi B, Bajbouj M, Hungs M, Ramaekers VT, Quasthoff S, Karch D, Schroder JM: X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1). J Neurol Sci. 1999, 167 (2): 90-101.PubMedGoogle Scholar
  202. Martin PE, Mambetisaeva ET, Archer DA, George CH, Evans WH: Analysis of gap junction assembly using mutated connexins detected in Charcot-Marie-Tooth X-linked disease. J Neurochem. 2000, 74 (2): 711-720.PubMedGoogle Scholar
  203. Wang HL, Chang WT, Yeh TH, Wu T, Chen MS, Wu CY: Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiol Dis. 2004, 15 (2): 361-370.PubMedGoogle Scholar
  204. Kleopa KA, Yum SW, Scherer SS: Cellular mechanisms of connexin32 mutations associated with CNS manifestations. J Neurosci Res. 2002, 68 (5): 522-534.PubMedGoogle Scholar
  205. Yum SW, Kleopa KA, Shumas S, Scherer SS: Diverse trafficking abnormalities of connexin32 mutants causing CMTX. Neurobiol Dis. 2002, 11 (1): 43-52.PubMedGoogle Scholar
  206. Dubourg O, Tardieu S, Birouk N, Gouider R, Leger JM, Maisonobe T, Brice A, Bouche P, LeGuern E: Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain. 2001, 124 (Pt 10): 1958-1967.PubMedGoogle Scholar
  207. Zhang Y, Hao H: Conserved glycine at position 45 of major cochlear connexins constitutes a vital component of the Ca(2)(+) sensor for gating of gap junction hemichannels. Biochem Biophys Res Commun. 2013, 436 (3): 424-429.PubMedGoogle Scholar
  208. Yoshimura T, Satake M, Ohnishi A, Tsutsumi Y, Fujikura Y: Mutations of connexin32 in Charcot-Marie-Tooth disease type X interfere with cell-to-cell communication but not cell proliferation and myelin-specific gene expression. J Neurosci Res. 1998, 51 (2): 154-161.PubMedGoogle Scholar
  209. Omori Y, Mesnil M, Yamasaki H: Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects. Mol Biol Cell. 1996, 7 (6): 907-916.PubMedPubMed CentralGoogle Scholar
  210. Abrams CK, Islam M, Mahmoud R, Kwon T, Bargiello TA, Freidin MM: Functional requirement for a highly conserved charged residue at position 75 in the gap junction protein connexin 32. J Biol Chem. 2013, 288 (5): 3609-3619.PubMedGoogle Scholar
  211. Janssen EA, Kemp S, Hensels GW, Sie OG, de Die-Smulders CE, Hoogendijk JE, et al. Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Hum Genet. 1997;99(4):501–5.PubMedGoogle Scholar
  212. Ri Y, Ballesteros JA, Abrams CK, Oh S, Verselis VK, Weinstein H, Bargiello TA: The role of a conserved proline residue in mediating conformational changes associated with voltage gating of Cx32 gap junctions. Biophys J. 1999, 76 (6): 2887-2898.PubMedPubMed CentralGoogle Scholar
  213. Abrams CK, Freidin M, Bukauskas F, Dobrenis K, Bargiello TA, Verselis VK, Bennett MV, Chen L, Sahenk Z: Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32. J neurosci: j Soc Neurosci. 2003, 23 (33): 10548-10558.Google Scholar
  214. Stauch K, Kieken F, Sorgen P: Characterization of the structure and intermolecular interactions between the connexin 32 carboxyl-terminal domain and the protein partners synapse-associated protein 97 and calmodulin. J Biol Chem. 2012, 287 (33): 27771-27788.PubMedPubMed CentralGoogle Scholar
  215. Jeng LJ, Balice-Gordon RJ, Messing A, Fischbeck KH, Scherer SS: The effects of a dominant connexin32 mutant in myelinating Schwann cells. Mol Cell Neurosci. 2006, 32 (3): 283-298.PubMedGoogle Scholar
  216. VanSlyke JK, Deschenes SM, Musil LS: Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. Mol Biol Cell. 2000, 11 (6): 1933-1946.PubMedPubMed CentralGoogle Scholar
  217. Fairweather N, Bell C, Cochrane S, Chelly J, Wang S, Mostacciuolo ML, Monaco AP, Haites NE: Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Hum Mol Genet. 1994, 3 (1): 29-34.PubMedGoogle Scholar
  218. Kleopa KA, Zamba-Papanicolaou E, Alevra X, Nicolaou P, Georgiou DM, Hadjisavvas A, Kyriakides T, Christodoulou K: Phenotypic and cellular expression of two novel connexin32 mutations causing CMT1X. Neurology. 2006, 66 (3): 396-402.PubMedGoogle Scholar
  219. Bruzzone R, White TW, Scherer SS, Fischbeck KH, Paul DL: Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease. Neuron. 1994, 13 (5): 1253-1260.PubMedGoogle Scholar
  220. Castro C, Gomez-Hernandez JM, Silander K, Barrio LC: Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations. J Neurosci. 1999, 19 (10): 3752-3760.PubMedGoogle Scholar
  221. Barrio LC, Castro C, Gomez-Hernandez JM: Altered assembly of gap junction channels caused by COOH-terminal connexin32 mutants of CMTX. Ann N Y Acad Sci. 1999, 883: 526-529.PubMedGoogle Scholar
  222. Hahn AF, Brown WF, Koopman WJ, Feasby TE: X-linked dominant hereditary motor and sensory neuropathy. Brain. 1990, 113 (Pt 5): 1511-1525.PubMedGoogle Scholar
  223. Shao Q, Liu Q, Lorentz R, Gong XQ, Bai D, Shaw GS, Laird DW: Structure and functional studies of N-terminal Cx43 mutants linked to oculodentodigital dysplasia. Mol Biol Cell. 2012, 23 (17): 3312-3321.PubMedPubMed CentralGoogle Scholar
  224. de la Parra DR, Zenteno JC: A new GJA1 (connexin 43) mutation causing oculodentodigital dysplasia associated to uncommon features. Ophthalmic Genet. 2007, 28 (4): 198-202.PubMedGoogle Scholar
  225. Kelly SC, Ratajczak P, Keller M, Purcell SM, Griffin T, Richard G: A novel GJA 1 mutation in oculo-dento-digital dysplasia with curly hair and hyperkeratosis. Eur J Dermatol. 2006, 16 (3): 241-245.PubMedGoogle Scholar
  226. Shibayama J, Paznekas W, Seki A, Taffet S, Jabs EW, Delmar M, Musa H: Functional characterization of connexin43 mutations found in patients with oculodentodigital dysplasia. Circ Res. 2005, 96 (10): e83-e91.PubMedGoogle Scholar
  227. Lai A, Le DN, Paznekas WA, Gifford WD, Jabs EW, Charles AC: Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells. J Cell Sci. 2006, 119 (Pt 3): 532-541.PubMedGoogle Scholar
  228. Paznekas WA, Karczeski B, Vermeer S, Lowry RB, Delatycki M, Laurence F, Koivisto PA, Van Maldergem L, Boyadjiev SA, Bodurtha JN, et al: GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Hum Mutat. 2009, 30 (5): 724-733.PubMedGoogle Scholar
  229. Richardson R, Donnai D, Meire F, Dixon MJ: Expression of Gja1 correlates with the phenotype observed in oculodentodigital syndrome/type III syndactyly. J Med Genet. 2004, 41 (1): 60-67.PubMedPubMed CentralGoogle Scholar
  230. Huang T, Shao Q, MacDonald A, Xin L, Lorentz R, Bai D, Laird DW: Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. J Cell Sci. 2013, 126 (Pt 13): 2857-2866.PubMedGoogle Scholar
  231. McLachlan E, Manias JL, Gong XQ, Lounsbury CS, Shao Q, Bernier SM, Bai D, Laird DW: Functional characterization of oculodentodigital dysplasia-associated Cx43 mutants. Cell Commun Adhes. 2005, 12 (5–6): 279-292.PubMedGoogle Scholar
  232. Van Norstrand DW, Asimaki A, Rubinos C, Dolmatova E, Srinivas M, Tester DJ, Saffitz JE, Duffy HS, Ackerman MJ: Connexin43 mutation causes heterogeneous gap junction loss and sudden infant death. Circulation. 2012, 125 (3): 474-481.PubMedGoogle Scholar
  233. Van Norstrand DW, Asimaki A, Rubinos C, Dolmatova E, Srinivas M, Tester DJ, Saffitz JE, Duffy HS, Ackerman MJ. The connexin 40 A96S mutation causes renin-dependent hypertension. J Am Soc Nephrol. 2011;22(6):1031–40.Google Scholar
  234. Kalcheva N, Qu J, Sandeep N, Garcia L, Zhang J, Wang Z, Lampe PD, Suadicani SO, Spray DC, Fishman GI: Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia. Proc Natl Acad Sci U S A. 2007, 104 (51): 20512-20516.PubMedPubMed CentralGoogle Scholar
  235. Hong HM, Yang JJ, Shieh JC, Lin ML, Li SY: Novel mutations in the connexin43 (GJA1) and GJA1 pseudogene may contribute to nonsyndromic hearing loss. Hum Genet. 2010, 127 (5): 545-551.PubMedGoogle Scholar
  236. Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B: A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Hum Mutat. 2004, 23 (3): 286PubMedGoogle Scholar
  237. Beahm DL, Oshima A, Gaietta GM, Hand GM, Smock AE, Zucker SN, Toloue MM, Chandrasekhar A, Nicholson BJ, Sosinsky GE: Mutation of a conserved threonine in the third transmembrane helix of alpha- and beta-connexins creates a dominant-negative closed gap junction channel. J Biol Chem. 2006, 281 (12): 7994-8009.PubMedGoogle Scholar
  238. Zucker SN, Bancroft TA, Place DE, Des Soye B, Bagati A, Berezney R: A dominant negative Cx43 mutant differentially affects tumorigenic and invasive properties in human metastatic melanoma cells. J Cell Physiol. 2013, 228 (4): 853-859.PubMedGoogle Scholar
  239. van Es RJ, Wittebol-Post D, Beemer FA: Oculodentodigital dysplasia with mandibular retrognathism and absence of syndactyly: a case report with a novel mutation in the connexin 43 gene. Int J Oral Maxillofac Surg. 2007, 36 (9): 858-860.PubMedGoogle Scholar
  240. Gong XQ, Shao Q, Lounsbury CS, Bai D, Laird DW: Functional characterization of a GJA1 frameshift mutation causing oculodentodigital dysplasia and palmoplantar keratoderma. J Biol Chem. 2006, 281 (42): 31801-31811.PubMedGoogle Scholar
  241. Dasgupta C, Martinez AM, Zuppan CW, Shah MM, Bailey LL, Fletcher WH: Identification of connexin43 (alpha1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (DGGE). Mutat Res. 2001, 479 (1–2): 173-186.PubMedGoogle Scholar
  242. Thomas BC, Minogue PJ, Valiunas V, Kanaporis G, Brink PR, Berthoud VM, Beyer EC: Cataracts are caused by alterations of a critical N-terminal positive charge in connexin50. Invest Ophthalmol Vis Sci. 2008, 49 (6): 2549-2556.PubMedPubMed CentralGoogle Scholar
  243. Zhu Y, Yu H, Wang W, Gong X, Yao K: Correction: A Novel GJA8 Mutation (p.V44A) Causing Autosomal Dominant Congenital Cataract. PLoS One. 2015, 10: e0125949PubMedPubMed CentralGoogle Scholar
  244. Vanita V, Singh JR, Singh D, Varon R, Sperling K: A novel mutation in GJA8 associated with jellyfish-like cataract in a family of Indian origin. Mol Vis. 2008, 14: 323-326.PubMedPubMed CentralGoogle Scholar
  245. Berry V, Mackay D, Khaliq S, Francis PJ, Hameed A, Anwar K, Mehdi SQ, Newbold RJ, Ionides A, Shiels A, et al: Connexin 50 mutation in a family with congenital “zonular nuclear” pulverulent cataract of Pakistani origin. Hum Genet. 1999, 105 (1–2): 168-170.PubMedGoogle Scholar
  246. Pal JD, Berthoud VM, Beyer EC, Mackay D, Shiels A, Ebihara L: Molecular mechanism underlying a Cx50-linked congenital cataract. Am J Phys. 1999, 276 (6 Pt 1): C1443-C1446.Google Scholar
  247. Arora A, Minogue PJ, Liu X, Reddy MA, Ainsworth JR, Bhattacharya SS, Webster AR, Hunt DM, Ebihara L, Moore AT, et al: A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract: further evidence for gap junction dysfunction in human cataract. J Med Genet. 2006, 43 (1): e2PubMedPubMed CentralGoogle Scholar
  248. Liu Y, Qiao C, Wei T, Zheng F, Guo S, Chen Q, et al. Mutant connexin 50 (S276F) inhibits channel and hemichannel functions inducing cataract. J Genet. 2015;94(2):221–9.PubMedGoogle Scholar
  249. Yan M, Xiong C, Ye SQ, Chen Y, Ke M, Zheng F, Zhou X: A novel connexin 50 (GJA8) mutation in a Chinese family with a dominant congenital pulverulent nuclear cataract. Mol Vis. 2008, 14: 418-424.PubMedPubMed CentralGoogle Scholar
  250. Minogue PJ, Beyer EC, Berthoud VM: A connexin50 mutant, CX50fs, that causes cataracts is unstable, but is rescued by a proteasomal inhibitor. J Biol Chem. 2013, 288 (28): 20427-20434.PubMedPubMed CentralGoogle Scholar

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