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Carmignac, V. et al.

C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy.

OBJECTIVE: The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late-onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early-onset, recessive muscle and cardiac disorder. METHODS: Clinical and myopathological reevaluation of the five affected children, positional cloning, immunofluorescence, and Western blot studies were performed. RESULTS: All children presented with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy. Skeletal muscle biopsies showed minicores, centrally located nuclei, and/or dystrophic lesions. In each family, we identified a homozygous titin deletion in exons encoding the C-terminal M-line region. Both deletions cause a frameshift downstream of the titin kinase domain and protein truncation. Immunofluorescence confirmed that truncated titins lacking the C-terminal end were incorporated into sarcomeres. Calpain 3 was secondarily depleted. INTERPRETATION: M-line titin homozygous truncations cause the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle. These results expand the spectrum of early-onset myopathies and suggest that titin segments downstream of the kinase domain are dispensable for skeletal and cardiac muscle development, but are crucial for maintaining sarcomere integrity.[1]

References

C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Carmignac, V., Salih, M.A., Quijano-Roy, S., Marchand, S., Al Rayess, M.M., Mukhtar, M.M., Urtizberea, J.A., Labeit, S., Guicheney, P., Leturcq, F., Gautel, M., Fardeau, M., Campbell, K.P., Richard, I., Estournet, B., Ferreiro, A. Ann. Neurol. (2007) [Pubmed]

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