Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes.

H utchinson-Gilford Progeria Syndrome (HGPS, OMIM 176670), commonly called ‘‘progeria’’, occurs in <1 in 8 million births and displays striking features of ‘‘premature aging’’. 2 HGPS recapitulates most of the pathologies of normal aging at an accelerated rate, with sparing of the nervous system. Children with HGPS usually appear normal in early infancy, but at about six months of age begin to experience profound growth delay. Scalp hair, eyebrows, and eyelashes are typically lost resulting in total alopecia. A gradual, almost complete lipodystrophy begins in infancy, and the skin acquires an abnormally aged appearance with prominent veins. In some children osteolysis may affect the clavicles, terminal phalanges, and acetabulum, and sometimes even more severe bone deformities occur, including generalised osteoporosis leading to repeated fractures and degenerative joint changes leading to coxa valga and hip dislocation. Affected children as young as five years develop widespread atherosclerosis including the coronary arteries and aorta, often resulting in death by myocardial infarction or stroke in the early teens. Recently, the genetic basis for HGPS was shown to be heterozygosity for a de novo point mutation in LMNA codon 608 in exon 11 (c. 1824 C.T). This single base substitution partially activates a cryptic splice site, leading to an altered lamin A protein in which 50 amino acids near the carboxyl terminus are deleted. The LMNA gene codes for both lamin A and lamin C, but the mutation only affects the structure of lamin A because exon 11 of LMNA is not present in lamin C mRNA. HGPS is a recent member of the family of ‘‘laminopathies’’, disorders caused by mutations in LMNA. 15 Others include autosomal dominant (AD) and autosomal recessive (AR) Emery-Dreifuss muscular dystrophy type 2 (EDMD2), a form of AD dilated cardiomyopathy (CMD1A), AD Dunnigan-type familial partial lipodystrophy, AD limb girdle muscular dystrophy type 1B (LGMD1B), AR Charcot-Marie-Tooth disorder type 2B1 and AR mandibuloacral dysplasia (MAD). Most HGPS probands are heterozygous for LMNA G608G, but one atypical HGPS proband was found to have an E145K mutation 13 and one patient was a compound heterozygote for R471C and R527C mutations. Furthermore, a small subset of patients with features of the adult-onset premature aging disease Werner’s syndrome (WRN, OMIM 277700) but no mutations in the causative WRN/RECQL2 gene, were found to have novel heterozygous LMNA mutations. MAD has previously been considered as a progeroid disorder, 19 and so far one mutation in LMNA has been associated with this disease: R527H. Therefore, we decided to search for mutations in LMNA in atypical cases of HGPS as well as in other patients with features of premature aging.