title: Fhl1 W122S causes loss of protein function and late-onset mild myopathy.
abstract: A member of the four-and-a-half-LIM (FHL) domain protein family, FHL1, is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS) and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at three time points (3-5 months, 7-10 months and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7 to 10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to human patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice.
authors.affiliation: Department of Neurology Pediatric Clinic, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genoa, Genoa 16100, Italy and.
authors.forename: Valentina
authors.initials: V
authors.lastname: Emmanuele
authors.affiliation: Department of Neurology.
authors.forename: Akatsuki
authors.initials: A
authors.lastname: Kubota
authors.affiliation: Department of Neurology.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garcia-Diaz
authors.affiliation: Department of Neurology.
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.affiliation: Department of Neurology.
authors.forename: Hasan O
authors.initials: HO
authors.lastname: Akman
authors.affiliation: Departamento de Biología Celular, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universdad de Sevilla, 41013 Seville, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sánchez-Gutiérrez
authors.affiliation: Departamento de Biología Celular, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universdad de Sevilla, 41013 Seville, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Escudero
authors.affiliation: Department of Pathology and Cell Biology.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kariya
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.affiliation: Department of Neurology Department of Pathology and Cell Biology.
authors.forename: Kurenai
authors.initials: K
authors.lastname: Tanji
authors.affiliation: Department of Neurology.
authors.forename: Catarina M
authors.initials: CM
authors.lastname: Quinzii
authors.affiliation: Department of Neurology mh29@cumc.columbia.edu.
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
mesh_terms: D017668:Age of Onset; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005552:Forelimb / Q000473:pathology*; D055879:Gene Knock-In Techniques; D057898:Hemizygote; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology*
chemical_list: C486306:Fhl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins