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

Ann Neurol. 2007 Apr;61(4):340-51. doi: 10.1002/ana.21089.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Calpain / metabolism
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / mortality
  • Cardiomyopathies / pathology
  • Child
  • Chromosomes, Human, Pair 2
  • Connectin
  • DNA Mutational Analysis
  • Exons
  • Family Health*
  • Gene Deletion*
  • Genetic Linkage
  • Genotype
  • Humans
  • Male
  • Molecular Sequence Data
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Muscles / pathology
  • Muscles / ultrastructure
  • Phenotype
  • Protein Kinases / chemistry
  • Protein Kinases / genetics*
  • Protein Structure, Tertiary / genetics


  • Connectin
  • Muscle Proteins
  • TTN protein, human
  • Protein Kinases
  • CAPN3 protein, human
  • Calpain

Associated data

  • GENBANK/AJ277892
  • RefSeq/NM_133378