Abstract:
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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. |