Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro- Muscular Center

Abstract

X-linked recessive myotubular myopathy (XLMTM) is characterized by severe hypotonia and generalized muscle weakness, with impaired maturation of muscle fibres. The gene responsible, MTM1, was identified recently by positional cloning, and encodes a protein (myotubularin) with a tyrosine phosphatase domain (PTP). Myotubularin is highly conserved through evolution and defines a new family of putative tyrosine phosphatases in man. We report the identification of MTM1 mutations in 55 of 85 independent patients screened by single-strand conformation polymorphism for all the coding sequence. Large deletions were observed in only three patients. Five point mutations were found in multiple unrelated patients, accounting for 27% of the observed mutations. The possibility of detecting mutations and determining carrier status in a disease with a high proportion of sporadic cases is of importance for genetic counselling. More than half of XLMTM mutations are expected to inactivate the putative enzymatic activity of myotubularin, either by truncation or by missense mutations affecting the predicted PTP domain. Additional mutations are missenses clustered in two regions of the protein. Most of these affect amino acids conserved in the homologous yeast and Caenorhabditis elegans proteins, thus indicating the presence of other functional domains.

Protein Tyrosine Phosphatase-Like A Regulates Myoblast Proliferation and Differentiation through MyoG and the Cell Cycling Signaling Pathway

“…For example, mutations in myotubularin 1, a PTPase encoded by the MTM1 (myotubular myopathy) gene in humans, is responsible for X-linked centronuclear myopathy in humans and canines (8,35,36). Besides the typical PTPases, a new family of protein tyrosine phosphatase-like (PTPL) genes has been identified (26,62).…”

Phosphatase-Dead Myotubularin Ameliorates X-Linked Centronuclear Myopathy Phenotypes in Mice

“…Thus, this mutant could promote the correction of the Mtm1 KO mice phenotypes through a dominant-negative effect by blocking the access of effectors to PtdIns3 P and/or PtdIns(3,5) P 2 . To address this issue, we used the MTM1 S376N ( Mtm1 -SN) mutant associated to severe XLCNM [36]. The S376N mutation located in the catalytic site abrogates the in vitro phosphatase activity [12] and this inactive mutant was predicted to disrupt the substrates binding based on the myotubularin MTMR2 crystal structure [37].…”

Disrupted autophagy undermines skeletal muscle adaptation and integrity

“…Loss of function mutations in myotubularins, the lipid phosphatases that specifically dephosphorylate PI3P and PI(3,5)P2 at the D3 position, has been associated with defects in the inhibition of autophagy and myopathy (Fetalvero et al 2013). These include mutations in myotubularin 1 (MTM1) and myotubularin-related protein 14 (MTMR14) that are associated, respectively, with X-linked myotubular myopathy (Laporte et al 1997) and congenital disease centronuclear myopathy (Tosch et al 2006). Mutations in valosin-containing protein (VCP) cause inclusion body myopathy and Paget disease of the bone and have been shown to alter autophagosome maturation and autophagy impairment (Custer et al 2010; Tresse et al 2010).…”