title: Consequences of mutations within the C terminus of the FHL1 gene.
abstract: BACKGROUND
  Mutations in the four-and-a-half LIM domain 1 gene (FHL1) cause X-linked late-onset scapuloaxioperoneal myopathy characterized by postural muscle atrophy with rigid spine syndrome with pseudoathleticism/hypertrophy (XMPMA), reducing body myopathy (RBM), and scapuloperoneal myopathy. Divergences in these diseases are hitherto unclear; therefore, we searched for additional families to elucidate differences and similarities of these allelic FHL1opathies.
  
  
  METHODS
  Using genotyping and phenotyping (mutational analysis, muscle histopathology, and Western blotting) we characterized 10 affected men and 8 women from 7 families.
  
  
  RESULTS
  All patients displayed the XMPMA phenotype. In 1 family with a novel missense mutation, 2 affected men had an aneurysm of the sinus of Valsalva in addition. In 5 affected men and 2 affected women from 4 families, the C224W missense mutation in FHL1 was detected, which putatively disrupts the fourth LIM domain. In 3 other families with 5 affected men and 1 female, 2 novel missense variants and a novel splice-site mutation in the C terminus of FHL1 were found. Muscle morphology revealed mild to moderate degenerative myopathy with myofiber hypertrophy of both fiber types at younger age and cytoplasmic bodies in the majority of the samples. Reducing bodies, pathognomonic for RBM, were not found. Western blotting revealed no detectable FHL1A protein in our patients.
  
  
  CONCLUSIONS
  As a consequence of C terminal FHL1 gene mutations, the X-linked myopathy characterized by postural muscle atrophy (XMPMA) phenotype and morphotype with cytoplasmic bodies are found. In the spectrum of FHL1opathies, the preserved FHL1C protein is likely responsible for the moderate XMPMA phenotype compared with the more severe reducing body myopathy/scapuloperoneal myopathy phenotype.
authors.affiliation: Friedrich-Baur Institute, Department of Neurology, Ludwig-Maximilians University Munich, Ziemssenstr. 1a, 80336 Munich, Germany. bschoser@med.uni-muenchen.de
authors.forename: B
authors.initials: B
authors.lastname: Schoser
authors.forename: H H
authors.initials: HH
authors.lastname: Goebel
authors.forename: I
authors.initials: I
authors.lastname: Janisch
authors.forename: S
authors.initials: S
authors.lastname: Quasthoff
authors.forename: J
authors.initials: J
authors.lastname: Rother
authors.forename: M
authors.initials: M
authors.lastname: Bergmann
authors.forename: W
authors.initials: W
authors.lastname: Müller-Felber
authors.forename: C
authors.initials: C
authors.lastname: Windpassinger
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics*; D060588:LIM Domain Proteins; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009135:Muscular Diseases / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000235:genetics; D055815:Young Adult
chemical_list: C101149:FHL1 protein, human; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins