Résumé :
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The first human titinopathies were identified in 2002. Five years later there is a wide variety of clinical phenotypes and mutational defects involved with titin mutations, such as selective cardiomyopathy, selective distal myopathy, LGMD phenotype, combined cardiomyopathy and skeletal muscular dystrophy and generalized myopathy with early respiratory failure. Dominant mutations causing selective cardiomyopathy are distributed all over different regions of the huge titin protein: both in the Z-disk, I-band and A-band parts of titin. Tibial muscular dystrophy (TMD), distal phenotype with rimmed vacuolar pathology, is caused by dominant mutations in the ultimate c-terminal last domains of titin. Missense, nonsense and complex mutations are known in different European populations. These mutations are capable of producing a completely different recessive LGMD phenotype without rimmed vacuolar pathology in homozygous individuals with TMD mutations. M-line portion of titin also contains a serine-threonine kinase, which is associated with a signaling complex including Nbr1, SQSTM and MuRF2 protein components. This signaling complex is a sensor of mechanical activity in the sarcomere, whereby MuRF2 can shuttle to the nucleus to interact with SRF and transcriptional regulation. A dominant mutation in the regulatory tail of this kinase distrupts the signaling complex and causes hereditary myopathy with early respiratory failure (HMERF) titinopathy disease with inclusion bodies and rimmed vacuoles on muscle biopsy. Recently truncating recessive mutations were identified in the fourth and sixth last exons of titin causing a severe lethal cardiomyopathy combined with generalized skeletal muscular dystrophy in two consanguineous families. The heterozygote parents with these mutations had no clinical phenotype. The story of titinopathies is by far not complete and many more phenotypes will be identified and associated with titin mutations. Many titinopathies show rimmed vacuolar pathology and in some cases abnormal aggregation of proteins causing differential diagnostic considerations regarding the group of myofibrillar myopathies.
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