Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contract ures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threate ning(1). Two modes of inheritance exist, X-linked (OMIM 310300) and autosom al dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease(2-4). Mutations in EMD, the gene encoding eme rin, are responsible for the X-linked form(5,6). We have mapped the locus f or EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French ped igree, and found that the EMD phenotype in four other small families was po tentially linked to this locus. This region contains the lamin A/C gene (LM NA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing(7,8). We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5 ,6), they underscore the potential importance of the nuclear envelope compo nents in the pathogenesis of neuromuscular disorders.