title: Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy.
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.
authors.affiliation: INSERM, U974, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Gueneau
authors.forename: Anne T
authors.initials: AT
authors.lastname: Bertrand
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jais
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.forename: Tanya
authors.initials: T
authors.lastname: Stojkovic
authors.forename: Manfred
authors.initials: M
authors.lastname: Wehnert
authors.forename: Maria
authors.initials: M
authors.lastname: Hoeltzenbein
authors.forename: Simone
authors.initials: S
authors.lastname: Spuler
authors.forename: Shinji
authors.initials: S
authors.lastname: Saitoh
authors.forename: Annie
authors.initials: A
authors.lastname: Verschueren
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.forename: Maud
authors.initials: M
authors.lastname: Beuvin
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lacene
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Rabah
authors.initials: R
authors.lastname: Ben Yaou
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
mesh_terms: D000293:Adolescent; D000328:Adult; D002318:Cardiovascular Diseases / Q000150:complications; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D050172:Genes, X-Linked; D055106:Genome-Wide Association Study; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D060588:LIM Domain Proteins; D008126:Lod Score; D008171:Lung Diseases / Q000150:complications; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D032446:Myoblasts / Q000473:pathology; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics; D012518:Sarcomeres / Q000473:pathology
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms