title: Intranuclear rod myopathy: molecular pathogenesis and mechanisms of weakness.
abstract: OBJECTIVE
  Mutations in the alpha-skeletal actin gene (ACTA1) result in a variety of inherited muscle disorders characterized by different pathologies and variable clinical phenotypes. Mutations at Val163 in ACTA1 result in pure intranuclear rod myopathy; however, the molecular mechanisms by which mutations at Val163 lead to intranuclear rod formation and muscle weakness are unknown.
  
  
  RESULTS
  We investigated the effects of the Val163Met mutation in ACTA1 in tissue culture and Drosophila models, and in patient muscle. In cultured cells, the mutant actin tends to aggregate rather than incorporate into cytoplasmic microfilaments, and it affects the dynamics of wild-type actin, causing it to accumulate with the mutant actin in the nucleus. In Drosophila, the Val163Met mutation severely disrupts the structure of the muscle sarcomere. The intranuclear aggregates in patient muscle biopsies impact on nuclear structure and sequester normal Z-disc-associated proteins within the nucleus; however, the sarcomeric structure is relatively well preserved, with evidence of active regeneration. By mass spectrometry, the levels of mutant protein are markedly reduced in patient muscle compared with control.
  
  
  CONCLUSIONS
  Data from our tissue culture and Drosophila models show that the Val163Met mutation in alpha-skeletal actin can affect the dynamics of other actin isoforms and severely disrupt sarcomeric structure, processes that can contribute to muscle weakness. However, in human muscle, there is evidence of regeneration, and the mutant protein tends to aggregate rather than incorporate into cytoplasmic microfilaments in cells. These are likely compensatory processes that ameliorate the effects of the mutant actin and contribute to the milder clinical and pathological disease phenotype.
authors: Institute for Neuromuscular Research, Children's Hospital at Westmead, New South Wales, Australia.
authors: Ana
authors: A
authors: Domazetovska
authors: Biljana
authors: B
authors: Ilkovski
authors: Vikash
authors: V
authors: Kumar
authors: Valentina A
authors: VA
authors: Valova
authors: Aurelie
authors: A
authors: Vandebrouck
authors: David O
authors: DO
authors: Hutchinson
authors: Phillip J
authors: PJ
authors: Robinson
authors: Sandra T
authors: ST
authors: Cooper
authors: John C
authors: JC
authors: Sparrow
authors: Michelle
authors: M
authors: Peckham
authors: Kathryn N
authors: KN
authors: North
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000222:Adaptation, Physiological; D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004330:Drosophila; D006801:Humans; D008715:Methionine; D051379:Mice; D018908:Muscle Weakness / Q000209:etiology; D018482:Muscle, Skeletal / Q000503:physiopathology; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D012038:Regeneration; D012518:Sarcomeres / Q000473:pathology; D014162:Transfection; D014633:Valine
chemical_list: D000199:Actins; D020033:Protein Isoforms; D008715:Methionine; D014633:Valine