Résumé :
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In 1999, we reported the first LMNA gene mutations responsible for the autosomal forms of Emery-Dreifuss muscular dystrophy (EDMD), this gene encoding nuclear envelope proteins, the lamins A/C. Since then, a huge number of patients carrying LMNA mutations have been reported either in other striated muscle disorders (including LGMD1B and isolated cardiac disease), or in hereditary neuropathies, lipodystrophies and premature ageing syndromes. These disorders are collectively named laminopathies.We reviewed clinical and genetic data of LMNA gene mutation carriers (1950 mutation carriers, 941 families) including non published (386 mutation carriers, 215 families, 145 different mutations) as well as those reported in the literature since 1999 (726 families, 1564 mutation carriers, 317 different LMNA). By using the Universal-Mutation-Database database-LMNA tools, we looked for molecular epidemiology and phenotype/genotype correlations with a special focus on striated muscle laminopathies (SML). SML has been found in more than 58% of the mutation carriers (1135 patients) either as an isolated feature or as a part of a multisystem dystrophy syndrome. When isolated (1085 patients, 55.6% of mutation carriers), typical presentations such as EDMD, LGMD1B and isolate cardiac disease were found respectively in 20% (392 patients), 8.5% (167 patients) and 24% (473 patients) of the mutation carriers. LMNA gene mutations causing SML are spread along the entire gene with a maximum hit within exons 1 and 6, residues 377 and 453 being the most frequently affected (14% of all SML cases). The majority of them (75%, 848 mutations carriers) are missense or in frame deletion/insertions. Of note, 19.2% of SML causing mutations are non sense or out of frame deletion/insertions while this type of mutation represents only 8.4% of other type of laminopathies. Usually, there is a good correlation between the presence of a disease and a specific LMNA mutation. However, different mutations located at different functional domains of the lamins A/C can give rise to the same clinical condition. Conversely certain mutations can cause completely different diseases even within the same family. These finding suggest an important inter- and intra-familial phenotypic heterogeneity in SML as well as in laminopathies in general. The molecular bases of this heterogeneity remain to be addressed and represent probably one of the future challenges in this area.
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