LMNA, encoding lamin A/C, is mutated in partial lipodystrophy

The lipodystrophies are a group of disorders characterized by the absence o r reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) lo ss of fat occurs during the peri-pubertal phase(1,2). Additionally, variabl e degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated wi th predisposition to atherosclerotic disease(3). The PLD locus has been map ped to chromosome 1q with no evidence of genetic heterogeneity(4). We, and others, have refined the location to a 5.3-cM interval between markers D1S3 05 and D1S1600 (refs 5,6). Through a positional cloning approach we have id entified five different missense mutations in LMNA among ten kindreds and t hree individuals with PLD. The protein product of LMNA is lamin AIC, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dys trophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system diseases (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substit utions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.