Mutations of the FHL1 Gene Cause Emery-Dreifuss Muscular Dystrophy |
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Authors: | Lucie Gueneau,Anne T. Bertrand,Jean-Philippe Jais,Tanya Stojkovic,Manfred Wehnert,Simone Spuler,Annie Verschueren,Maud Beuvin,Emmanuelle Lacene,Norma B. Romero,Simon Heath,Thomas Voit,Bruno Eymard,Gisè le Bonne |
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Affiliation: | 1 INSERM, U974, Paris, F-75013, France 2 Université Pierre et Marie Curie-Paris, UMR-S974, CNRS, UMR-7215, Institut de Myologie, IFR14, Paris, F-75013, France 3 Université Paris Descartes, EA 4067, Faculté de Médecine, Biostatistique et Informatique Médicale, GH Necker Enfants-Malades, Paris, F-75015, France 4 Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia 5 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de Référence des Maladies Rares Neuromusculaires, Paris, F-75013, France 6 Institute of Human Genetics, Greifswald, D-17487, Germany 7 Muscle Research Unit, Experimental and Clinical Research Center, Charité University Medicine Berlin, D-13125, Germany 8 Hokkaido University Graduate School of Medicine, Department of Pediatrics, Sapporo, 060-8638, Japan 9 AP-HM, Hôpital de la Timone, Service de Neurologie et Maladies Neurologiques, Marseille, F-13000, France 10 Service de Neurologie, Hôpitaux Universitaires, Strasbourg, F-67000, France 11 Association Institut de Myologie, Unité de Morphologie Neuromusculaire, Groupe Hospitalier Pitié-Salpêtrière, Paris, F-75013, France 12 Centre National de Génotypage, Evry, F-91000, France 13 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, F-75013, France |
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Abstract: | Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias. So far, only 35% of EDMD cases are genetically elucidated and associated with EMD or LMNA gene mutations, suggesting the existence of additional major genes. By whole-genome scan, we identified linkage to the Xq26.3 locus containing the FHL1 gene in three informative families belonging to our EMD- and LMNA-negative cohort. Analysis of the FHL1 gene identified seven mutations, in the distal exons of FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families. Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy. Interestingly, four of the FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two. Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available. In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy. |
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