title: C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, France.
authors: Virginie
authors: V
authors: Carmignac
authors: Mustafa A M
authors: MA
authors: Salih
authors: Susana
authors: S
authors: Quijano-Roy
authors: Sylvie
authors: S
authors: Marchand
authors: Molham M
authors: MM
authors: Al Rayess
authors: Maowia M
authors: MM
authors: Mukhtar
authors: Jon A
authors: JA
authors: Urtizberea
authors: Siegfried
authors: S
authors: Labeit
authors: Pascale
authors: P
authors: Guicheney
authors: France
authors: F
authors: Leturcq
authors: Mathias
authors: M
authors: Gautel
authors: Michel
authors: M
authors: Fardeau
authors: Kevin P
authors: KP
authors: Campbell
authors: Isabelle
authors: I
authors: Richard
authors: Brigitte
authors: B
authors: Estournet
authors: Ana
authors: A
authors: Ferreiro
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002154:Calpain / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002648:Child; D002889:Chromosomes, Human, Pair 2; D064211:Connectin; D004252:DNA Mutational Analysis; D005091:Exons; D005192:Family Health; D017353:Gene Deletion; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009132:Muscles / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases; C105884:CAPN3 protein, human; D002154:Calpain