Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS; MIM 176670) is an extremely rare genetic disorder displaying features reminiscent of premature senescence.1,2 Typically, affected children appear normal at birth, but begin to develop characteristic symptoms within the first years of life such as failure to thrive, alopecia, lipodystrophy, and scleroderma-like skin changes. Though the first HGPS cases were described more than 100 years ago,1,3 its extreme rarity (1:4–8 000 000) and mostly sporadic occurrence made it difficult to identify the underlying genetic cause. By means of homozygosity mapping as well as candidate gene analysis, two research groups recently reported that heterozygous, recurrent de novo point mutations in the lamin A/C gene ( LMNA ; MIM 150330), a component of the filamentous meshwork of the nuclear lamina, caused HGPS.4,5 LMNA encodes two A-type lamins, lamin A and C, which are the result of alternative splicing and share the first 566 amino acids.6,7 Together with B-type lamins, they represent the main components of the nuclear lamina. In contrast to B-type lamins, which are ubiquitously expressed in all cell types at all developmental stages, A-type lamins are absent in the cells of the early embryo, embryonic stem cells, stem cells of the immune and haematopoietic systems as well as in cells of the neuroendocrine system (reviewed in Goldman et al 8 and Mounkes et al 9). Besides HGPS, germline mutations in LMNA have been shown to cause seven phenotypically different disorders, inherited in an autosomal dominant and/or recessive manner.4,5,10 Considering the tissue(s) affected, they can be grouped into those involving mainly (i) striated and cardiac muscle, (ii) peripheral nerves, and (iii) white adipose tissue and bones.9 Together with HGPS, two of them belong to the so-called progeroid syndromes: an atypical form of Werner syndrome (WRN; …