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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References
Emery, A.E. Emery-Dreifuss syndrome. J. Med. Genet. 26, 637–641 (1989).
Fenichel, G.M., Sul, Y.C., Kilroy, A.W. & Blouin, R. An autosomal-dominant dystrophy with humeropelvic distribution and cardiomyopathy. Neurology 32, 1399–1401 ( 1982).
Miller, R.G. et al. Emery-Dreifuss muscular dystrophy with autosomal dominant transmission. Neurology 35, 1230– 1233 (1985).
Yates, J.R. 43rd ENMC international workshop on Emery-Dreifuss muscular dystrophy, 22 June 1996, Naarden, The Netherlands. Neuromuscul. Disord. 7, 67–69 (1997).
Bione, S. et al. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nature Genet. 8, 323 –327 (1994).
Nagano, A. et al. Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy. Nature Genet. 12 , 254–259 (1996).
Lin, F. & Worman, H.J. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J. Biol. Chem. 268, 16321–16326 (1993).
Wydner, K.L., McNeil, J.A., Lin, F., Worman, H.J. & Lawrence, J.B. Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization. Genomics 32, 474–478 (1996).
Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152– 154 (1996).
van der Kooi, A.J. et al. Genetic localization of a newly recognized autosomal dominant limb-girdle muscular dystrophy with cardiac involvement (LGMD1B) to chromosome 1q11-21. Am. J. Hum. Genet. 60, 891–895 (1997).
Bushby, K.M. & Beckmann, J.S. The limb-girdle muscular dystrophies—proposal for a new nomenclature. Neuromuscul. Disord. 5, 337–343 (1995).
van der Kooi, A.J. et al. A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement. Ann. Neurol. 39 , 636–642 (1996).
Fisher, D.Z., Chaudhary, N. & Blobel, G. cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins. Proc. Natl Acad. Sci. USA 83, 6450– 6454 (1986).
McKeon, F.D., Kirschner, M.W. & Caput, D. Homologies in both primary and secondary structure between nuclear envelope and intermediate filament proteins. Nature 319, 463–468 (1986).
Guilly, M.N., Bensussan, A., Bourge, J.F., Bornens, M. & Courvalin, J.C. A human T lymphoblastic cell line lacks lamins A and C. EMBO J. 6, 3795 –3799 (1987).
Guilly, M.N., Kolb, J.P., Gosti, F., Godeau, F. & Courvalin, J.C. Lamins A and C are not expressed at early stages of human lymphocyte differentiation. Exp. Cell Res. 189 , 145–147 (1990).
Rober, R.A., Sauter, H., Weber, K. & Osborn, M. Cells of the cellular immune and hemopoietic system of the mouse lack lamins A/C: distinction versus other somatic cells. J. Cell Sci. 95, 587 –598 (1990).
Worman, H.J., Evans, C.D. & Blobel, G. The lamin B receptor of the nuclear envelope inner membrane: a polytopic protein with eight potential transmembrane domains. J. Cell Biol. 111, 1535–1542 (1990).
Furukawa, K., Pante, N., Aebi, U. & Gerace, L. Cloning of a cDNA for lamina-associated polypeptide 2 (LAP2) and identification of regions that specify targeting to the nuclear envelope. EMBO J. 14, 1626–1636 (1995).
Martin, L., Crimaudo, C. & Gerace, L. cDNA cloning and characterization of lamina-associated polypeptide 1C (LAP1C), an integral protein of the inner nuclear membrane. J. Biol. Chem. 270, 8822– 8828 (1995).
Squarzoni, S. et al. Immunocytochemical detection of emerin within the nuclear matrix. Neuromuscul. Disord. 8, 338– 344 (1998).
Glass, C.A. et al. The α-helical rod domain of human lamins A and C contains a chromatin binding site. EMBO J. 12, 4413 –4424 (1993).
Taniura, H., Glass, C. & Gerace, L. A chromatin binding site in the tail domain of nuclear lamins that interacts with core histones. J. Cell Biol. 131, 33–44 (1995).
Hoger, T.H., Krohne, G. & Kleinschmidt, J.A. Interaction of Xenopus lamins A and LII with chromatin in vitro mediated by a sequence element in the carboxyterminal domain. Exp. Cell Res. 197, 280–289 (1991).
Speer, M.C. et al. Confirmation of genetic heterogeneity in limb-girdle muscular dystrophy: linkage of an autosomal dominant form to chromosome 5q. Am. J. Hum. Genet. 50, 1211–1217 (1992).
Vicart, P. et al. A missense mutation in the α B-crystallin chaperone gene causes a desmin-related myopathy. Nature Genet. 20, 92–95 (1998).
Carrier, L. et al. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ. Res. 80, 427–434 (1997).
Cartegni, L. et al. Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy. Hum. Mol. Genet. 6, 2257–2264 (1997).
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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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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DOI: https://doi.org/10.1038/6799
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