Genomic organization of the MTM1 gene implicated in X-linked myotubular myopathy

Abstract

X-linked recessive myotubular myopathy (XLMTM) is a very severe congenital muscular disease characterised by an impaired maturation of muscle fibres, and caused by defects in the MTM1 gene. This gene defines a new family of putative tyrosine phosphatases conserved through evolution. We have determined intronic flanking sequences for all the 15 exons to facilitate the detection of mutations in patients and genetic counselling. We characterised a new polymorphic marker in the immediate vicinity of the gene, which might prove useful for linkage analysis. Sequencing of the TATA-less predicted promoter provides the basis for transcriptional regulatory studies.

Identification of novel mutations in theMTM1 gene causing severe and mild forms of X-linked myotubular myopathy

“…DNA was then purified using the Microspin 400 column (Pharmacia Biotech) and sequenced on either ABI 310 or ABI 377 sequencers (Applied Biosystems) using the same primers as for PCR. Sequence changes were identified by comparing with the MTM1 cDNA sequence (Genbank, U46024) or with the splice junctions of the MTM1 gene [Laporte et al, 1998a].…”

“…The MTM1 gene has been isolated by positional cloning . It is about 100 kb in length and is composed of 15 exons [Laporte et al, 1998a]. It encodes a 603-amino acid protein, myotubularin, that contains the consensus active site of protein tyrosine phosphatases (PTP) and displays a dual specificity phosphatase (DSP) activity in vitro [Cui et al, 1998;Laporte et al, 1998b].…”

Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate

“…As a first step toward understanding the molecular basis of myotubular myopathy, we have examined the effects of MTM1 mutations associated with severe forms of the disorder on myotubularin phosphatase activity (9,41). Although several of the mutations that have been identified are predicted to affect myotubularin phosphatase activity, a definitive analysis of the enzymatic properties of these mutants toward a physiologic substrate has not been reported.…”

“…Myotubularin contains the Cys-X 5 -Arg (CX 5 R) active site motif that is the hallmark of the protein tyrosine phosphatase (PTP) superfamily and exhibits dual specificity protein phosphatase activity in vitro (6)(7)(8)(9). In addition, myotubularin-related proteins are conserved among eukaryotes, suggesting a common substrate or function (5,9). However, the physiologic target(s) of myotubularin and its essential role in myogenic development have yet to be identified.…”

“…The myotubularin gene (MTM1), which is mutated in X-linked myotubular myopathy, encodes a protein with sequence similarity to dual specificity protein tyrosine phosphatases (5). Myotubularin contains the Cys-X 5 -Arg (CX 5 R) active site motif that is the hallmark of the protein tyrosine phosphatase (PTP) superfamily and exhibits dual specificity protein phosphatase activity in vitro (6)(7)(8)(9). In addition, myotubularin-related proteins are conserved among eukaryotes, suggesting a common substrate or function (5,9).…”