| Résumé : | The FHL1 gene, localized on the X chromosome, encodes the Four and a Half LIM proteins 1, proteins belonging to a protein family containing LIM domains (Lin-11, Isl-1, Mec3), that are highly conserved sequences constituted by two zinc fingers in tandem, implicated in numerous interactions. Three isoforms are produced via alternative splicing of the FHL1 gene, FHL1A, B and C. FHL1 proteins can be localized to the sarcolemma, sarcomere, and nucleus of muscle cells. The functions of FHL1 in striated muscle remain largely unknown. FHL1A has been described as playing an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via activation of the ERK pathway or via the regulation of cytoskeleton organization and integrin signalling pathway. FHL1 proteins may also participate in several steps of myoblast differentiation as FHL1B and FHL1C isoforms contain a RBP-J binding domain that prevent RBP-J transcription factor (a mediator of Notch signalling) from binding to its specific target genes.Recently, FHL1 mutations have been identified as the cause of four distinct skeletal muscle diseases. Since the first report in 2008, over 25 different mutations have been identified in patients with reducing body myopathy (RBM), X-linked myopathy with postural muscle atrophy (XMPMA), scapuloperoneal myopathy (SPM) and EmeryDreifuss muscular dystrophy (EDMD). RBM is characterized by progressive muscle weakness and the presence of intracytoplasmic aggregates termed "reducing bodies" observed in muscle biopsies; its underlying genetic cause was unknown until the discovery of FHL1 mutations. XMPMA is characterized by late-onset scapulo-axio-peroneal myopathy, postural muscle atrophy and generalized hypertrophy are only caused by FHL1 mutations so far. SPM is characterized by slowly progressive shoulder-girdle and peroneal muscles weakness and atrophy. Distinct subtypes of SPM are caused by mutations in the DES (desmin), MYH7 (myosin heavy chain) and FHL1 genes. Finally, EDMD is characterized by early joint contractures, muscular dystrophy, and cardiac disease with conduction defects and arrhythmias and can be caused for the autosomal forms by mutations in the LMNA (lamins A/C) gene and for the X-linked forms by mutations in the EMD (emerin) or FHL1 genes. Review and update of these FHL1-associated disorders, with a comprehensive analysis of mutations, comparison of the clinical and histopathological features and current hypotheses for the possible disease mechanisms will be discussed. |
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