title: A novel mutation in FHL1 in a family with X-linked scapuloperoneal myopathy: phenotypic spectrum and structural study of FHL1 mutations.
abstract: An X-linked myopathy was recently associated with mutations in the four-and-a-half-LIM domains 1 (FHL1) gene. We identified a family with late onset, slowly progressive weakness of scapuloperoneal muscles in three brothers and their mother. A novel missense mutation in the LIM2 domain of FHL1 (W122C) co-segregated with disease in the family. The phenotype was less severe than that in other reported families. Muscle biopsy revealed myopathic changes with FHL1 inclusions that were ubiquitin- and desmin-positive. This mutation provides additional evidence for X-linked myopathy caused by a narrow spectrum of mutations in FHL1, mostly in the LIM2 domain. Molecular dynamics (MD) simulations of the newly identified mutation and five previously published missense mutations in the LIM2 domain revealed no major distortions of the protein structure or disruption of zinc binding. There were, however, increases in the nonpolar, solvent-accessible surface area in one or both of two clusters of residues, suggesting that the mutant proteins have a variably increased propensity to aggregate. Review of the literature shows a wide range of phenotypes associated with mutations in FHL1. However, recognizing the typical scapuloperoneal phenotype and X-linked inheritance pattern will help clinicians arrive at the correct diagnosis.
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, USA.
authors.forename: Dong-Hui
authors.initials: DH
authors.lastname: Chen
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.forename: William W
authors.initials: WW
authors.lastname: Parson
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Sonnen
authors.forename: Tiffany
authors.initials: T
authors.lastname: Vu
authors.forename: Yunlin
authors.initials: Y
authors.lastname: Zheng
authors.forename: Mark
authors.initials: M
authors.lastname: Matsushita
authors.forename: John
authors.initials: J
authors.lastname: Wolff
authors.forename: Hillary
authors.initials: H
authors.lastname: Lipe
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D020233:Gait Disorders, Neurologic / Q000473:pathology / Q000503:physiopathology; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D008040:Genetic Linkage / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011487:Protein Conformation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D055815:Young Adult
chemical_list: C101149:FHL1 protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C085473:LHX1 protein, human; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors