Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare sporadic disorder with an incidence of 1 per 8 million live births. Birth weight and appearance are usually normal, but growth typically becomes retarded at the age of 1 year. Phenotypic features include short stature, sculptured nose, alopecia, prominent scalp veins, small face, subcutaneous fat loss, faint mid-facial cyanosis, and dystrophic nails. Features occurring in the skin during late adulthood of normal individuals, such as hair greying, hair loss, and skin thinning, occur in the first few years of life in subjects with HGPS [1–3]. Most subjects die in their teenage years from cardiac complications of coronary artery disease or stroke due to widespread arteriosclerosis .
The diagnosis of HGPS was formerly based on the criteria of growth retardation and prematurely aged phenotype in children. In 2003, however, mutations in the LMNA gene that encodes nuclear lamins A and C were identified as responsible for this syndrome [4–6]. As such, HGPS belongs to the group of diseases caused by mutations in LMNA, sometimes referred to as "laminopathies," which also includes disorders of striated muscle, peripheral nerve and partial lipodystrophy syndromes [7, 8]. The LMNA mutation present in the majority of subjects with HGPS is a de novo heterozygous base change (GGC>GGT) within exon 11 of the LMNA gene, which does not cause an amino acid substitution (G608G) but creates an abnormal splice donor site [4, 5].
Nuclear lamins are members of the intermediate filament protein superfamily [9, 10]. They are the building blocks of the nuclear lamina, a fibrous proteinaceous meshwork underlying the inner nuclear membrane . Nuclear lamins have an extra 42 amino acids (six heptads) in coil 1B compared to cytoplasmic intermediate filament proteins [12, 13]. Nuclear lamins also contain two unique sequences: a nuclear localization signal in the tail domain , and, except for lamin C, a carboxyl-terminal CAAX box (cysteine-aliphatic-aliphatic-any amino acid), a target for isoprenylation [15–18]. In the human genome, 3 distinct loci encode lamins. LMNA is located on chromosome 1q21.2 [19, 20] and encodes 4 lamins by alternative RNA splicing: A, C, AΔ10, and C2 . Lamin A is synthesized as a precursor, prelamin A, from which 17 amino acids are removed from the carboxyl-terminal by endoproteolysis after isoprenylation. There are 2 B-type lamin genes: LMNB1 on chromosome 5q23-q31.1 that encodes lamin B1 [20, 22], and LMNB2 on chromosome 19p13.3  that encodes lamin B2  and lamin B3, an alternatively spliced isoform expressed in germ cells .
We recently identified a new female subject with HGPS from Italy. We now show that she has the most common heterozygous point mutation, G608G, in LMNA resulting in expression of the prelamin A mutant with 50 amino acids deleted from the carboxyl-terminal tail domain. We analyzed the nuclear morphology and growth characteristics of these fibroblasts, and for the first time demonstrate that cells from a subject with HGPS exhibit increased susceptibility to heat stress.