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Multitissular involvement in a family with LMNA and EMD mutations

Role of digenic mechanism?

From Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 582 (R.B.Y., T.A., C.M., A.M., G.B.) and Université Pierre et Marie Curie–Paris6, Institut de Myologie, UMR S582, IFR14 (R.B.Y., T.A., C.M., A.M., G.B.) and Assistance Publ Hop Paris, Groupe Hospitalier Pitié–Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie métabolique (L.D., P.R., G.B.), and Assistance Publ Hop Paris, Hôpital Cochin, Laboratorie de Biochimie et Génétique Moléculaire (C.P., S.L., N.D., F.L., D.R.-B.), Paris, and Service de Génétique (A.T.), Hôpital Bretonneau, CHU, Service de Cardiologie B (D.B.), Hôpital Trousseau, CHU, Tours, France; and Oran (K.E.L., N.R.-C.), Algeria.

Address correspondence and reprint requests to Dr. G. Bonne, INSERM U582–Institut de Myologie, Groupe Hospitalier Pitié–Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France g.bonne{at}myologie.chups.jussieu.fr

Background: Mutations in the EMD and LMNA genes, encoding emerin and lamins A and C, are responsible for the X-linked and autosomal dominant and recessive forms of Emery–Dreifuss muscular dystrophy (EDMD). LMNA mutations can also lead to several other disorders, collectively termed laminopathies, involving heart, fat, nerve, bone, and skin tissues, and some premature ageing syndromes.

Methods: Fourteen members of a single family underwent neurologic, electromyographic, and cardiologic assessment. Gene mutation and protein expression analyses were performed for lamins A/C and emerin.

Results: Clinical investigations showed various phenotypes, including isolated cardiac disease (seven patients), axonal neuropathy (one patient), and a combination of EDMD with axonal neuropathy (two patients), whereas five subjects remained asymptomatic. Genetic analyses identified the coincidence of a previously described homozygous LMNA mutation (c.892CT, p. R298C) and a new in-frame EMD deletion (c.110-112delAGA, p. delK37), which segregate independently. Analyses of the contribution of these mutations showed 1) the EMD codon deletion acts in X-linked dominant fashion and was sufficient to induce the cardiac disease, 2) the combination of both the hemizygous EMD and the homozygous LMNA mutations was necessary to induce the EDMD phenotype, 3) emerin was present in reduced amount in EMD-mutated cells, and 4) lamin A/C and emerin expression was most dramatically affected in the doubly mutated fibroblasts.

Conclusions: This highlights the crucial role of lamin A/C–emerin interactions, with evidence for synergistic effects of these mutations that lead to Emery–Dreifuss muscular dystrophy as the worsened result of digenic mechanism in this family.

Editorial, see page 1879

Supported by grants from the European Union Sixth Framework (Euro-laminopathies, contract no. 018690), INSERM/AFM (Association Française contre les Myopathies) French rare disease network "EDMD and other nucleopathies" (contract no. 4MR06F, AFM grant no. 10722), Human Frontiers Science Program (HFSPO grant no. RGP0057/2001-M101), grants in aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, research grants from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), Ichiro Kanehara Foundation, and HFSPO grant no. RGP0057 and AFM grant no. 11737 (T.A.).

Disclosure: The authors report no conflicts of interest.

Received August 3, 2006. Accepted in final form February 2, 2007.

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