The lamins are a group of intermediate filament proteins which form major components of the nuclear lamina in most differentiated eukaryotic cells. The expression of lamins is developmentally regulated but most cell types in the adult body contain A- and B-type lamins (for review see ). In humans, three genes, LMNA, LMNB1 and LMNB2, encode distinct subtypes of proteins. The LMNA gene gives rise to lamins A and C by alternative splicing . Lamins B1 and B2 are encoded by the two LMNB genes and are constitutively expressed independently of developmental stage. The expression of lamin B3, a splice variant of lamin B2, is limited to germ cells. In order to build up the nuclear lamina, lamins form homo- and heteropolymers which associate with other proteins into a network that underlies and supports the nuclear membrane (for review see ).
The lamins came into the focus of clinical interest when the LMNA gene was found to cause a rare heritable progressive myopathy, the autosomal-dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD, OMIM #181350; ). Another variant of this disease which is transmitted as an X-linked trait (X-EDMD, OMIM # 310300), had been earlier associated to mutations in emerin, a transmembrane protein of the inner nuclear membrane . Thus, EDMD was the first disease found to be due to defects in proteins of the nuclear envelope. Clinically, the two variants are quite similar and are characterised by (1) a progressive muscular weakness with humero-peroneal distribution, (2) early contractures of the Achilles tendon, the elbows and the post-cervical muscles, and (3) atrial arrhythmias and/or a cardiomyopathy. A combination of these three cardinal symptoms is rarely seen in other myopathies and appears to be a discriminating feature of EDMD. Typically, symptoms develop in the second decade of life with the contractures often preceding clinically significant weakness. In young patients, the cardiac arrhythmia may go unnoticed and can lead to sudden death by cardiac arrest. Therefore, an early diagnosis is potentially life saving, since heart function can be stabilised by implantation of a cardiac pace maker .
In the past years, defects in the LMNA gene have been recognised to cause a pleiotropy of clinical phenotypes in 3 other autosomal dominant and 3 recessive disorders: (i) a form of limb-girdle muscular dystrophy with cardiac conduction defects (LGMD1B, OMIM #159001; ); (ii) a dilated cardiomyopathy with conduction defects (CMD1A; OMIM #115200; ), (iii) a familial partial lipodystrophy (FPLD; OMIM #151660; [9, 10]); (iv) a recessive form of EDMD , (v) an autosomal recessive axonal neuropathy (Charcot-Marie-Tooth disease 2B1; CMT2B1; OMIM #605588; [12, 13]) and (vi) mandibuloacral dysplasia (MAD; OMIM #248370, ). Recently, dominant de novo mutations have been shown to cause the Hutchinson-Gilford progeria (HPGS; OMIM #176670, [15, 16]). Furthermore, an association of a LMNA polymorphism to quantitative determinants of obesity was reported . A review of the published mutations, mostly heterozygous amino acid replacements, suggested that interactions of specific domains of the lamin A/C protein with as yet unknown proteins may lead to the spectrum of tissue-specific mutations [11, 18, 19]. In the case of Emery-Dreifuss muscular dystrophy mutations are found mainly in the C-terminal domain of the protein leading to disturbance of dimerisation and fusion of the dimers to filaments [17, 20]. A direct interaction between emerin and the lamins could be shown [21, 22]. Moreover, mutations in either one of these proteins cause similar clinical symptoms indicating a strong interaction within a common function.
Despite numerous observations, up to now there is no conclusive explanation for the tissue-specific effect of the mutations in the emerin-lamin A/C complex. Although the proteins are expressed ubiquitously, mutations lead to primary cell damage and pathology in very specific cell types only whereas in most other tissues the mutations show no effect.
Progressive muscle wasting in EDMD is the result of a failure of adequate muscle regeneration. Muscle fibres destroyed by mechanical stress cannot be reconstituted by a sufficient amount of newly differentiated myotubes. This leads to a decrease of muscle mass and subsequent weakness . According to one hypothesis, the function of the emerin-lamin A/C complex is the stabilisation of the nuclear envelope . This may be of particular importance in cells which are subject to mechanical stress like muscle cells . The disturbance of this stabilizing system and the resulting cell death in the affected muscle could, thus, explain the clinical symptoms of the disease.
The mutations in the lamin A-gene which have been analysed in detail  show different, partly position dependent effects like mislocalization of lamin A (R453W) or lamin C (E358K), and an apparent reduction of emerin expression in the nucleus (R527P; [26, 27]). This could compromise the structural stability of the nucleus as a consequence of the altered lamina [28, 29]. In other mutations like L530P, a wild-type distribution of lamin A, lamin C and emerin was observed . These results could indicate that in this case another so far unknown function of lamin A and/or emerin is disturbed. Recently a role of lamin A and associated proteins in gene expression has been postulated . Furthermore, cDNA microarray analysis has revealed changes in gene expression in X-EDMD fibroblasts .
We had the rare opportunity to study three different cell types from one AD-EDMD patient (99-3) carrying a point mutation in the rod domain of the LMNA gene which replaces arginine 377 by histidine (R377H). In the present study we used lymphoblasts, myoblasts, skin fibroblasts and muscle thin sections to examine the effects of this mutation on nuclear structure and proteins. Our results show that the mutation LMNA R377H causes defects in lamin A stability and assembly which can extend to an aberrant nuclear phenotype. We further demonstrate a mislocalization of LBR and RNA pol II in the patient's cells.