title: A rising titan: TTN review and mutation update.
abstract: The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical, and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to the widespread use of NGS, TTN is emerging as a major gene in human-inherited disease. So far, 127 TTN disease-causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes, or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. In this review, we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern, and phenotype-genotype correlations, alongside with their implications for basic research and for human health.
authors: Inserm, U787 Myology Group, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; UPMC, UMR787, Paris, France.
authors: Claire
authors: C
authors: Chauveau
authors: John
authors: J
authors: Rowell
authors: Ana
authors: A
authors: Ferreiro
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D064211:Connectin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D056726:Genetic Association Studies; D014644:Genetic Variation; D005828:Genetics, Population; D006801:Humans; D040582:Inheritance Patterns; D009154:Mutation; D020033:Protein Isoforms; D013329:Structure-Activity Relationship
chemical_list: D064211:Connectin; D020033:Protein Isoforms; C577285:TTN protein, human
keywords: TTN; genotype-phenotype correlation; titin; titinopathies