CHARACTERIZATION OF THE MYOTUBULARIN DUAL-SPECIFICITY PHOSPHATASE GENE FAMILY FROM YEAST TO HUMAN

X-linked myotubular myopathy (XLMTM) is a severe congenital muscle dis order due to mutations in the MTM1 gene. The corresponding protein, my otubalarin, contains the consensus active site of tyrosine phosphatase s (PTP) but otherwise shows no homology to other phosphatases. Myotubu larin is able to hydrolyze a synthetic analogue of tyrosine phosphate, in a reaction inhibited by orthovanadate, and was recently shown to a ct on both phosphotyrosine and phosphoserine. This gene is conserved d own to yeast and strong homologies were found with human ESTs, thus de fining a new dual specificity phosphatase (DSP) family, We report the presence of novel members of the MT'M gene family in Schizosaccharomyc es pombe, Caenorhabditis elegans, zebrafish, Drosophila, mouse and man . This represents the largest family of DSPs described to date, Eight MTM-related genes were found in the human genome and we determined the chrome,somal localization and expression pattern for most of them, A subclass of the myotubularin homologues lacks a functional PTP active site. Missense mutations found in XLMTM patients affect residues conse rved in a Drosophila homologue, Comparison of the various genes allowe d construction of a phylogenetic tree and reveals conserved residues w hich may be essential for function. These genes may be good candidates for other genetic diseases.