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By mass spectrometry, the levels of mutant protein are markedly reduced in patient muscle compared with control.InterpretationData from our tissue culture and Drosophila models show that the Val163Met mutation in α-skeletal actin can affect the dynamics of other actin isoforms and severely disrupt sarcomeric structure, processes that can contribute to muscle weakness. 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. In Drosophila, the Val163Met mutation severely disrupts the structure of the muscle sarcomere. 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. By mass spectrometry, the levels of mutant protein are markedly reduced in patient muscle compared with control.We investigated the effects of the Val163Met mutation in ACTA1 in tissue culture and Drosophila models, and in patient muscle.

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.Methods and ResultsWe investigated the effects of the Val163Met mutation in ACTA1 in tissue culture and Drosophila models, and in patient muscle. 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.Mutations in the α-skeletal actin gene (ACTA1) result in a variety of inherited muscle disorders characterized by different pathologies and variable clinical phenotypes.

ObjectiveMutations in the α-skeletal actin gene (ACTA1) result in a variety of inherited muscle disorders characterized by different pathologies and variable clinical phenotypes.