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Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy

Item Type:Article
Title:Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy
Creators Name:Gueneau, L. and Bertrand, A.T. and Jais, J.P. and Salih, M.A. and Stojkovic, T. and Wehnert, M. and Hoeltzenbein, M. and Spuler, S. and Saitoh, S. and Verschueren, A. and Tranchant, C. and Beuvin, M. and Lacene, E. and Romero, N.B. and Heath, S. and Zelenika, D. and Voit, T. and Eymard, B. and Ben Yaou, R. and Bonne, G.
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.
Keywords:Cardiovascular Diseases, Cell Differentiation, X Human Chromosomes, Cohort Studies, DNA Mutational Analysis, Fluorescent Antibody Technique, X-Linked Genes, Genome-Wide Association Study, Immunoblotting, Intracellular Signaling Peptides and Proteins, Lod Score, Lung Diseases, Muscle Proteins, Emery-Dreifuss Muscular Dystrophy, Mutation, Myoblasts, Pedigree, Protein Isoforms, Sarcomeres
Source:American Journal of Human Genetics
ISSN:0002-9297
Publisher:University of Chicago Press (U.S.A.)
Volume:85
Number:3
Page Range:338-353
Date:September 2009
Official Publication:https://doi.org/10.1016/j.ajhg.2009.07.015
PubMed:View item in PubMed

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