MTM1 mutations in X-linked myotubular myopathy

X-linked myotubular myopathy (XLMTM; MIM# 310400) is a severe congenital mu scle disorder caused by mutations in the MTM1 gene. This gene encodes a dua l-specificity phosphatase named myotubularin, defining a large gene family highly conserved through evolution (which includes the putative anti phosph atase Sbf1/hMTMR5). We report 29 mutations in novel cases, including 16 mut ations not described before. To date, 198 mutations have been identified in unrelated families, accounting for 133 different disease-associated mutati ons which are widespread throughout the gene. Most point mutations are trun cating, but 26% (35/133) are missense mutations affecting residues conserve d in the Drosophila ortholog and in the homologous MTMR1 gene. Three recurr ent mutations affect 17% of the patients, and a total of 21 different mutat ions were found in several independent families. The frequency of female ca rriers appears higher than expected (only 17% are de novo mutations). While most truncating mutations cause the severe and early lethal phenotype, som e missense mutations are associated with milder forms and prolonged surviva l (up to 54 years). Hum Mutat 15:393-409, 2000. (C) 2000 Wiley-Liss, Inc.