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

Abstract

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening1. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease2,3,4. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form5,6. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing7,8. 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 components in the pathogenesis of neuromuscular disorders.

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Figure 1: Identification of point mutations in LMNA.
Figure 2: LMNA mutations in EDMD-AD patients characterized by DNA sequencing.
Figure 3: Transverse cryostat sections of cardiac muscle from a patient of family EMD1 (a,c) carrying a nonsense LMNA mutation and from a control individual (b,d).
Figure 4: Amino acid sequences alignment of lamins A, B and C from various species.

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Acknowledgements

We thank the family members for participation; J. Dopf for the analysis of family EMD4; J. Beckmann for collaboration with GénéthonII; D. Recan for DNA samples of family EMD1; M. Petit and H. Collin for their genotyping and immunohistochemical analysis; and J.-C. Courvalin for lamin A/C antibody and for critically reading the manuscript. This work was supported by INSERM, the Association Française contre les Myopathies (grant 6100) and the Telethon Italy (grant E297). We also thank the European Neuromuscular Center (ENMC) for its continuous support.

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Correspondence to Gisèle Bonne or Ketty Schwartz.

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Bonne, G., Barletta, M., Varnous, S. et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 21, 285–288 (1999). https://doi.org/10.1038/6799

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