title: The pathogenesis of ACTA1-related congenital fiber type disproportion.
abstract: OBJECTIVE
  Mutations in ACTA1 have been associated with a variety of changes in muscle histology that likely result from fundamental differences in the way that ACTA1 mutations disrupt muscle function. Recently, we reported three patients with congenital fiber type disproportion (CFTD) caused by novel heterozygous missense mutations in ACTA1 (D292V, L221P, P332S) with marked type 1 fiber hypotrophy as the only pathological finding on muscle biopsy. We have investigated the basis for the histological differences between these CFTD patients and patients with ACTA1 nemaline myopathy (NM).
  
  
  RESULTS
  Mass spectrometry and two-dimensional gel electrophoresis demonstrate that mutant actin accounts for 25 and 50% of alpha-skeletal actin in the skeletal muscle of patients with the P332S and D292V mutations, respectively, consistent with a dominant-negative disease mechanism. In vitro motility studies indicate that abnormal interactions between actin and tropomyosin are the likely principal cause of muscle weakness for D292V, with tropomyosin stabilized in the "switched off" position. Both the D292V and P322S CFTD mutations are associated with normal sarcomeric structure on electron microscopy, which is atypical for severe NM. In contrast, we found no clear difference between ACTA1 mutations associated with NM and CFTD in tendency to polymerize or aggregate in C2C12 expression models.
  
  
  CONCLUSIONS
  These data suggest that ACTA1 CFTD mutations cause weakness by disrupting sarcomere function rather than structure. We raise the possibility that the presence or absence of structural disorganization when mutant actin incorporates into sarcomeres may be an important determinant of whether the histological patterns of CFTD or NM develop in ACTA1 myopathy.
authors: Institute for Neuromuscular Research, Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, New South Wales, Australia.
authors: Nigel F
authors: NF
authors: Clarke
authors: Biljana
authors: B
authors: Ilkovski
authors: Sandra
authors: S
authors: Cooper
authors: Valentina A
authors: VA
authors: Valova
authors: Phillip J
authors: PJ
authors: Robinson
authors: Ikuya
authors: I
authors: Nonaka
authors: Juan-Juan
authors: JJ
authors: Feng
authors: Steven
authors: S
authors: Marston
authors: Kathryn
authors: K
authors: North
mesh_terms: D000199:Actins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001706:Biopsy; D002460:Cell Line; D002675:Child, Preschool; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D018908:Muscle Weakness / Q000235:genetics; D018482:Muscle, Skeletal / Q000737:chemistry / Q000473:pathology*; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000473:pathology*; D015879:Myosin Subfragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D012518:Sarcomeres / Q000737:chemistry / Q000648:ultrastructure; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
chemical_list: D000199:Actins; D046912:Multiprotein Complexes; D015879:Myosin Subfragments