HGNC Approved Gene Symbol: MTM1
SNOMEDCT: 46804001; ICD10CM: G71.220;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:150,562,653-150,673,143 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Myopathy, centronuclear, X-linked | 310400 | X-linked recessive | 3 |
The MTM1 gene encodes a protein that belongs to a family of putative tyrosine phosphatases. Myotubularin is required for muscle cell differentiation. Myotubularin is also a potent phosphatidylinositol 3-phosphate (PI3P) phosphatase (Blondeau et al., 2000; Taylor et al., 2000).
According to Laporte et al. (1998), 8 different genes encoding human myotubularin-related proteins had been reported: MTMR1 (300171) on Xq28; MTMR2 (603557) on 11q22; MTMR3 (603558) on 22q12; MTMR4 (603559) on chromosome 17; SBF1, also known as MTMR5 (603560), on 22qter; MTMR6 (603561) on 13q12; MTMR7 (603562) on 8p22; and MTMR8 (MTMR9; 606260) on 8p23-p22.
A consortium of 3 groups (Laporte et al., 1996) reported the isolation and characterization of the MTM1 gene (Laporte et al., 1996). They restricted the candidate region for the gene mutated in X-linked myotubular myopathy-1 (XLMTM; 310400) to 280 kb and then used positional cloning to characterize a 3.4-kb cDNA that encodes at least 621 amino acids and a polyadenylation site. Additional clones from liver and skeletal muscle showed an alternative upstream polyadenylation site. The protein encoded by the MTM1 gene, designated myotubularin, was found to be highly conserved in yeast. The protein contains the consensus sequence for the active site of tyrosine phosphatases, a wide class of proteins involved in signal transduction. Preliminary Northern analysis showed ubiquitous expression of a 3.9-kb MTM1 transcript, while a 2.4-kb message was detected in skeletal muscle and testis. Both the high conservation in yeast and the ubiquitous expression of the MTM1 transcript contrasted strikingly with the apparent muscle specificity of the disease myotubular myopathy. Laporte et al. (1996) stated that at least 3 other genes, 1 located within 100 kb distal from the MTM1 gene, encode proteins with very high sequence similarities and define, together with the MTM1 gene, a new family of putative tyrosine phosphatases (PTPs) in man. Kioschis et al. (1996) constructed a 900-kb cosmid contig including the entire MTM1 candidate region and identified 10 new transcripts within the region.
By positional cloning, Laporte et al. (1996) mapped the MTM1 gene to Xq28.
Kioschis et al. (1998) determined that the MTM1 and MTMR1 genes are transcribed in the same direction and are separated by 20 kb. Analysis of the genomic region containing MTM1 and MTMR1 suggested that the 2 genes are related and arose from an intrachromosomal gene duplication. The authors stated that other examples of intrachromosomal gene duplication in Xq28 include the IDS (300823) gene duplication and a cluster of MAGE genes (see 300016).
As part of an effort to clone the MTM1 gene, de Gouyon et al. (1996) developed a YAC contig of the mouse X chromosome which included loci homologous to those within the human MTM1 critical region, a 300-kb interval between IDS (300823) and GABRA3 (305660) on Xq28. They aligned the human and murine physical maps by isolating conserved mouse genomic fragments, including CpG islands and trapped exons.
The SET (Suvar3-9, Enhancer of zeste, trithorax) domain was originally identified as a characteristic motif in several Drosophila proteins that contribute to epigenetic mechanisms of gene regulation. The human protooncoprotein HRX (159555) also contains a SET domain. Cui et al. (1998) determined that MTM1 and SBF1 (603560) interacted with HRX in vitro and in vivo. This interaction was abrogated in an oncogenic form of HRX lacking the SET domain. Like HRX, both SBF1 and MTM1 localized to the nucleus of mammalian cells. The authors found that MTM1 and SBF1 have a conserved SET interaction domain (SID) that displays a paired amphipathic helix secondary structure. In contrast with MTM1, SBF1 lacked dual-specificity phosphatase activity in vitro, suggesting that SBF1 acts as a protective factor that prevents substrate dephosphorylation. Ectopic expression of SBF1 impaired the in vitro differentiation of myoblast cells, implying that interactions of SET-domain proteins with catalytically active members of the myotubularin family are essential for execution of the myogenic program. The authors stated that these results are consistent with the adverse effects of inherited MTM1 loss-of-function mutations on muscle maturation in X-linked myotubular myopathy (XLMTM). They concluded that myotubularin proteins link SET domain-containing components of the epigenetic regulatory machinery with signaling pathways involved in differentiation.
Taylor et al. (2000) reported that myotubularin, a protein-tyrosine phosphatase required for muscle cell differentiation, is a potent phosphatidylinositol 3-phosphate (PI3P) phosphatase. They found that mutations in the MTM1 gene that cause human myotubular myopathy dramatically reduced the ability of the phosphatase to dephosphorylate PI3P. The findings provided evidence that myotubularin exerts its effects during myogenesis by regulating the cellular levels of the inositol lipid PI3P.
Blondeau et al. (2000) investigated the activity and substrate specificity of MTM1. Expression of active human myotubularin inhibited growth of S. pombe and induced a vacuolar phenotype similar to that of mutants of the vacuolar protein sorting (VPS) pathway and notably of mutants of VPS34, a phosphatidylinositol 3-kinase (PI3K; see 602838). In S. pombe cells deleted for the endogenous MTM homologous gene, expression of human myotubularin decreased the level of phosphatidylinositol 3-phosphate (PI3P). A substrate trap mutant relocalized to plasma membrane projections (spikes) in HeLa cells and was inactive in the S. pombe assay. This mutant, but not the wildtype or a phosphatase site mutant, was able to immunoprecipitate a VPS34 kinase activity. Wildtype myotubularin was also able to directly dephosphorylate PI3P and PI4P in vitro. The authors hypothesized that myotubularin may decrease PI3P levels by downregulating PI3K activity and by directly degrading PI3P.
Laporte et al. (2001) provided an extensive review of the myotubularin-related genes. These genes define a large family of eukaryotic proteins, most of which were initially characterized by the presence of a 10-amino acid consensus sequence related to the active sites of tyrosine phosphatases, dual-specificity protein phosphatases, and the lipid phosphatase PTEN (601728). MTM1 is the founding member of the family. A close homolog, MTMR2 (603557), is mutated in a recessive form of Charcot-Marie-Tooth neuropathy (601382). Laporte et al. (2001) pointed out that although myotubularin was thought to be a dual-specificity protein phosphatase, studies indicate that it is primarily a lipid phosphatase, acting on phosphatidylinositol 3-monophosphate, and possibly involved in the regulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway and membrane trafficking.
Nandurkar et al. (2003) identified myotubularin as the catalytically active 3-phosphatase subunit interacting with 3PAP (606501). Recombinant myotubularin localized to the plasma membrane, causing extensive filopodia formation. However, coexpression of 3PAP with myotubularin led to attenuation of the plasma membrane phenotype, associated with myotubularin relocalization to the cytosol. Collectively these studies indicated that 3PAP functions as an 'adaptor' for myotubularin, regulating myotubularin intracellular location and thereby altering the phenotype resulting from myotubularin overexpression.
Ketel et al. (2016) reported that surface delivery of endosomal cargo requires hydrolysis of PI(3)P by the phosphatidylinositol 3-phosphatase MTM1, an enzyme whose loss of function leads to X-linked centronuclear myopathy (also called myotubular myopathy) in humans. Removal of endosomal PI(3)P by MTM1 is accompanied by phosphatidylinositol 4-kinase-2-alpha (PI4K2-alpha)-dependent generation of PI(4)P and recruitment of the exocyst tethering complex to enable membrane fusion. Ketel et al. (2016) concluded that their data established a mechanism for phosphoinositide conversion from PI(3)P to PI(4)P at endosomes en route to the plasma membrane and suggested that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by mutation of MTM1 in humans.
In a male with XLMTM, Laporte et al. (1996) demonstrated an A-to-G transition at nucleotide 620 predicting a substitution of serine for asparagine-207 in the MTM1 gene (300415.0001). This was 1 of 4 missense mutations that, together with 3 frameshift mutations, were found in 7 of 60 MTM1 patients studied.
By direct genomic sequencing of 92% of the known coding sequence of the myotubularin gene, de Gouyon et al. (1997) identified mutations in 26 of 41 unrelated male patients with muscle biopsy-proven myotubular myopathy. Point mutations were found in 18 patients, including an A-to-G transition found in 4 patients, which altered a splice acceptor site in exon 12 and led to a 3-amino acid insertion. Six patients had small deletions involving less than 6 bp, while 2 larger deletions encompassed 2 and 6 exons, respectively. All 5 patients with a mild phenotype had missense mutations (e.g., 300415.0003). While 50% of the mutations were found in exons 4 and 12, and 3 distinct mutations were found in more than 1 patient, no single mutation accounted for more than 10% of the cases. Low frequency of large deletions and the varied mutations identified suggested to de Gouyon et al. (1997) that direct mutation screening for molecular diagnosis may require gene sequencing.
Simultaneously, a consortium of 3 groups of investigators (Laporte et al., 1997) reported the identification of MTM1 mutations in 55 of 85 unrelated patients screened by SSCP for all the coding sequence. Large deletions were observed in only 3 patients. Five point mutations were found in multiple unrelated patients, accounting for 27% of the observed mutations. More than half of the mutations were expected to inactivate the putative enzymatic activity of myotubularin, either by truncation or by missense mutations affecting the predicted protein tyrosine phosphatase domain. Laporte et al. (1997) suggested that there are likely to be other functional domains of the protein since additional missense mutations were clustered in 2 regions of the protein where the affected amino acids are conserved in yeast and C. elegans.
In 3 families previously investigated by linkage analysis, Tanner et al. (1998) identified 3 new mutations in the MTM1 gene as the cause of X-linked recessive myotubular myopathy: an acceptor splice site mutation (300415.0004), a frameshift mutation (300415.0005), and an intronic mutation involving a cryptic splice site (300415.0006).
Buj-Bello et al. (1999) reported the identification of 21 mutations (14 novel) in XLMTM patients. Seventeen mutations were associated with a severe phenotype. The other 4 mutations (3 missense and 1 single-amino acid deletion) were found in patients with a much milder phenotype; although all of them had severe hypotonia at birth, the hypotonia improved with age.
Laporte et al. (1998) determined intronic flanking sequences for all 15 exons of the MTM1 gene to facilitate the detection of mutations in patients and genetic counseling. They characterized a new polymorphic marker in the immediate vicinity of the gene that might prove useful for linkage analysis. Laporte et al. (2000) reported 29 mutations in cases of myotubular myopathy, including 16 novel mutations. They stated that 198 mutations had been identified in unrelated families, accounting for 133 different disease-associated mutations widely distributed throughout the gene. Most of the point mutations were truncating, but 26% (35 of 133) were missense mutations affecting residues conserved in the Drosophila ortholog and in the homologous MTMR1 gene. Three recurrent mutations affected 17% of the patients, and a total of 21 mutations were found in several independent families. The frequency of female carriers appeared higher than expected; only 17% were de novo mutations. Whereas most truncating mutations caused a severe and early lethal phenotype, some missense mutations were associated with milder forms and prolonged survival, up to 54 years in the first reported family (Van Wijngaarden et al., 1969; Barth and Dubowitz, 1998).
Herman et al. (2002) stated that 133 different mutations had been identified in the MTM1 gene worldwide. They reported mutations detected in 50 additional U.S. families with biopsy-proven MTM1. Eighteen novel mutations were identified in 41 patients who had not previously been described. Eighty-eight percent of the mothers of sporadic cases studied were identified as carriers.
Tsai et al. (2005) reported 31 Japanese patients with myotubular myopathy caused by mutation in the MTM1 gene, and identified 14 novel mutations. Truncating mutations and gene-abolishing large deletions accounted for 52% of the mutations. A splice site mutation (300415.0006) was identified in 3 unrelated patients, suggesting it is a mutation hotspot.
To understand the pathophysiologic mechanism of XLMTM, Buj-Bello et al. (2002) generated mice lacking myotubularin by homologous recombination. These mice were viable, but their life span was severely reduced. They developed a generalized and progressive myopathy starting at approximately 4 weeks of age, with amyotrophy and accumulation of central nuclei in skeletal muscle fibers leading to death at 6 to 14 weeks of age. Buj-Bello et al. (2002) showed that muscle differentiation in knockout mice occurred normally, contrary to expectations. They provided evidence that fibers with centralized myonuclei originate mainly from a structural maintenance defect affecting myotubularin-deficient muscle rather than a regenerative process. In addition, they demonstrated through a conditional gene-targeting approach that skeletal muscle is the primary target of murine XLMTM pathology.
Dowling et al. (2009) observed that zebrafish with reduced levels of myotubularin had significantly impaired motor function and obvious histopathologic muscle changes, including abnormally shaped and positioned nuclei and myofiber hypotrophy, as observed in the human disease. Loss of myotubularin caused increased PI3P levels in muscle in vivo. Morpholino knockdown of Mtm1 in zebrafish muscle resulted in abnormalities in the T-tubule and sarcoplasmic reticulum network, similar to T-tubule disorganization observed in patients with myotubular myopathy. Expression of the homologous myotubularin-related proteins Mtmr1 and Mtmr2 could functionally compensate for the loss of myotubularin in zebrafish. Dowling et al. (2009) suggested that XLMTM may be linked mechanistically by tubuloreticular abnormalities and defective excitation-contraction coupling to myopathies caused by mutations in the RYR1 gene (180901).
Fetalvero et al. (2013) found that Mtm1 -/- skeletal muscle showed increased content of PI3P, ubiquitinated proteins, and lipidated proteins normally degraded via autophagy. Mtm1 -/- skeletal muscle also showed accumulation of defective mitochondria with decreased COX enzyme activity and elevated activity of mTORC1 (see 601231), a major nutrient sensor and autophagy inhibitor. No change in mTORC1, mitochondria, or content of nondegraded proteins was observed in liver, heart, or brain of Mtm1 -/- mice. Overnight fasting activated mTORC1-dependent inhibition of autophagy in wildtype, but not Mtm1 -/-, skeletal muscle. Inhibition of hyperactivated mTORC1 normalized autophagy and rescued muscle mass in Mtm1 -/- mice. Fetalvero et al. (2013) concluded that MTM1 is involved in regulation of mTORC1 and autophagy.
Cowling et al. (2014) found a 1.5-fold increase in DNM2 (602378) expression in muscle biopsies isolated from human patients with CNMX (XLMTM) and in heterozygous Mtm1 -/y mice compared to controls. Crossing Mtm1 -/y with Dnm2 +/- mice resulted in increased survival and greatly improved muscle strength, suggesting that reduced expression of the Dnm2 gene can rescue the early lethality observed in Mtm1 -/y mice. Skeletal muscle from the double-mutant mice showed decreased or even rescued atrophy compared to Mtm1 -/y mice, and histologic abnormalities such as fiber atrophy and nuclei mispositioning were absent or reduced in the double-mutant mice. Ultrastructural analysis showed improvement of sarcomere organization and triad structures. In addition, muscle-specific reduction of Dnm2, particularly in the diaphragm, was sufficient to rescue the lethal phenotype even after birth and the onset of symptoms. The findings indicated that MTM1 and DNM2 regulate muscle organization and force through a common pathway, and suggested that MTM1 may act as a negative regulator of DNM2. Cowling et al. (2014) concluded that reduction of DNM2 protein levels may provide a therapeutic approach for patients with CNMX.
In a male with X-linked myotubular myopathy (CNMX; 310400), Laporte et al. (1996) demonstrated an A-to-G transition of nucleotide 620 predicting a substitution of serine for asparagine-207 in the MTM1 gene. This was 1 of 4 missense mutations that, together with 3 frameshift mutations, were found in 7 of 60 MTM1 patients studied.
In an affected individual thought to have a form of X-linked myotubular myopathy (CNMX; 310400) distinct from the Xq28 form (Samson et al., 1995), Guiraud-Chaumeil et al. (1997) found a single basepair change, 1244A-G, resulting in a change of tyrosine-415 to cysteine in the predicted protein (called myotubularin by them). This tyrosine coded in exon c (Laporte et al., 1996) is close to the putative tyrosine phosphatase active site (positions 389 to 402) and is conserved in the homologs of myotubularin in both yeast and C. elegans.
In 3 patients with X-linked myotubular myopathy (CNMX; 310400) studied by de Gouyon et al. (1997) and in 1 patient studied by Laporte et al. (1997), a C-to-T transition of nucleotide 259 in the MTM1 gene was identified, predicted to result in an arg69-to-cys (R69C) amino acid substitution. The patient of Laporte et al. (1997) was still alive at 3 years of age; 2 of the patients reported by de Gouyon et al. (1997) were known to have had a mild phenotype and 1 of them had an affected uncle. This mutation was associated with a CpG dinucleotide.
In a family with X-linked myotubular myopathy (CNMX; 310400), Tanner et al. (1998) identified a G-to-A transition in the acceptor splice site of intron 8 (at nucleotide 733-1).
In a family with X-linked myotubular myopathy (CNMX; 310400), Tanner et al. (1998) identified a 4-bp deletion (195delAGAA) leading to a frameshift at amino acid position 66. The mutation was expected to result in a premature stop codon and truncation of the MTM1 gene product.
In a family with X-linked myotubular myopathy (CNMX; 310400), Tanner et al. (1998) found that an A-to-G transition in intron 11 (nucleotide 1315-10) cosegregated with the haplotype associated with the MTM1 phenotype. It was presumed that a cryptic splice site existed at nucleotide position 1315-10. RT-PCR of muscle derived RNA from the patient and subsequent sequencing of the obtained products proved that splicing occurred at the new splice site. This predicted the insertion of 3 amino acids (FIQ) in frame between exon c and exon 12 in a conserved region of the protein.
In the tabulation of Laporte et al. (2000), this was the most frequent mutation found in the MTM1 gene in cases of X-linked myotubular myopathy and causes a severe myopathy.
In the tabulation of Laporte et al. (2000), the second most frequent recurrent mutation in the MTM1 gene in X-linked myotubular myopathy (CNMX; 310400) was a C-to-T transition at nucleotide 721, resulting in an arg241-to-cys amino acid substitution. The phenotype was mild in 5 patients (with 3 patients still alive at age 4 years) and severe in 2 patients.
Sutton et al. (2001) described a family with X-linked myotubular myopathy (CNMX; 310400) in which the index male was hemizygous for an arg224-to-ter (R224X) mutation in exon 8 of the MTM1 gene. The mother and maternal grandmother were obligate carriers according to linkage analysis, but neither showed any clinical manifestations of a myopathy. On the other hand, a maternal aunt had noted difficulty climbing stairs at the age of 5 years followed by progressive wasting and weakness of proximal limb muscles. Facial weakness beginning at the age of 8 years resulted in mild dysarthria. At the age of 13 years she was noted to have scoliosis. Examination at the age of 29 years showed bilateral facial weakness, proximal limb-girdle wasting and weakness, and bilateral weakness of the tibialis anterior. There was no weakness of extraocular movements. Creatine kinase was elevated at 203 IU/L. Although a skewed pattern of X-chromosome inactivation was suspected, such was detected in either the lymphocyte or muscle DNA of the woman, who was found to be heterozygous for the R224X mutation.
Schara et al. (2003) reported a female with prenatal/neonatal onset of clinical symptoms due to myotubular myopathy (CNMX; 310400). During pregnancy, fetal movements were reduced. After birth, she showed severe hypotonia, dyspnea, a weak cry, absent tendon reflexes, a high-arched palate, and a right-sided ptosis. She later had limb-girdle and facial muscle weakness and a waddling gait. Skeletal muscle biopsy showed a wide variation of fiber size and numerous internal nuclei. Direct sequencing of the MTM1 gene showed a heterozygous frameshift mutation, 605delT. Schara et al. (2003) noted the more severe clinical course in this female compared to other reported affected females and emphasized the prenatal onset of symptoms.
In a family with an unusually mild form of X-linked myotubular myopathy (CNMX; 310400), as indicated by 3 males surviving into adulthood, Yu et al. (2003) identified a 469G-A transition in exon 7 of the MTM1 gene, resulting in a glu157-to-lys (E157K) substitution. There was no neonatal or infant mortality resulting from the myopathy. One affected male did not have neonatal asphyxia, had normal early motor milestones, and was able to increase his muscle mass and strength to normal by weight lifting. Another affected male, 55 years of age, lived independently. Two other families, each with a mild phenotype caused by a missense mutation in the MTM1 gene and multiple adult survivors, had previously been described (Barth and Dubowitz, 1998; Biancalana et al., 2003).
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