title: Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene.
abstract: Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery-Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here, we report on three British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3-bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.forename: Judith
authors.initials: J
authors.lastname: Hudson
authors.forename: Charlotte F
authors.initials: CF
authors.lastname: Dougan
authors.forename: Bryan
authors.initials: B
authors.lastname: Lecky
authors.forename: David
authors.initials: D
authors.lastname: Hilton-Jones
authors.forename: Michelle
authors.initials: M
authors.lastname: Eagle
authors.forename: Richard
authors.initials: R
authors.lastname: Charlton
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
mesh_terms: D000328:Adult; D001706:Biopsy; D005091:Exons; D005190:Family; D005260:Female; D018703:Founder Effect; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D006113:United Kingdom
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins