Identification of novel mutations in the MTM1 gene causing severe and mildforms of X-linked myotubular myopathy

X-linked myotubular myopathy (XLMTM) is a congenital muscular disease chara cterized by severe hypotonia and generalized muscle weakness, leading in mo st cases Po early postnatal death. The gene responsible for the disease, MT M1, encodes a dual specificity phosphatase, named myotubularin, which is hi ghly conserved throughout evolution. To date, 139 MTM1 mutations in indepen dent patients have been report-ed, corresponding to 93 different mutations, In this report we describe the identification of 21 mutations (14 novel) i n XLMTM patients. Seventeen mutations are associated with a severe phenotyp e in males, with death occurring mainly before the first year of life. Howe ver, four mutations-three missense (R241C, I225T, and novel mutation P1795) and one single-amino acid deletion (G294del)-were found in patients with a much milder phenotype. These patients, while having a severe hypotonia at birth, are still alive at the age of 4, 7, 13, and 15 years, respectively, and display mild to moderate muscle weakness. Hum Mutat 14:320-325, 1999, ( C) 1999 Wiley-Liss, Inc.