Alternative titles; symbols
HGNC Approved Gene Symbol: MTMR14
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:9,649,505-9,702,393 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.3 | {Centronuclear myopathy, autosomal, modifier of} | 160150 | Autosomal dominant | 3 |
The MTMR14 gene encodes a muscle-specific inositide phosphatase that acts specifically on phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), and possibly other targets, and plays a critical role in skeletal muscle calcium homeostasis and likely other cellular processes (summary by Romero-Suarez et al., 2010).
From a database screen for protein sequences similar to human myotubularin (300415), which is mutated in a form of centronuclear myopathy (CNMX; 310400), Tosch et al. (2006) identified a novel protein, MTMR14, with high homology to Drosophila egg-derived tyrosine phosphatase (EDTP). The authors called this protein hJUMPY because disruption of EDTP protein function in Drosophila causes a phenotype termed JUMPY: a muscle defect and a progressive loss of muscle control together with shaky and slower movements. The deduced 650-amino acid MTMR14 protein contains a predicted protein tyrosine phosphatase and dual-specificity phosphatase (PTP/DSP) domain and the canonical C(X)5R consensus present in active PTP/DSPs. The MTMR14 catalytic loop shows closest resemblance to that of active myotubularins. Northern blot analysis detected a 2.5-kb MTMR14 transcript with highest expression in skeletal muscle and heart and lower expression in placenta, kidney, liver, pancreas, and lung. Immunofluorescence studies showed that MTMR14 localizes to cytoplasmic reticular structures and plasma membrane ruffles, and displays a concentration near the nucleus of COS-1 cells. MTMR14 was more concentrated in structures positive for giantin (602500), a Golgi marker.
Shen et al. (2009) identified the MTMR14 protein as a phosphatase predominantly expressed in skeletal and heart muscle. The human and mouse proteins share 90% amino acid sequence homology.
By quantitative PCR in mice, Tosch et al. (2006) showed that expression of Mtmr14 increased with C2C12 myotubule formation and differentiation in culture. Using in vitro and ex vivo approaches, Tosch et al. (2006) demonstrated that MTMR14 is a PPIn 3-phosphatase that dephosphorylates the same substrates as myotubularin, PtdIns(3)P and PtdIns(3,5)P2.
Shen et al. (2009) also demonstrated that MTMR14 dephosphorylates a variety of PtdInsPs, particularly PtdIns(3,5)P2.
Tosch et al. (2006) determined that the MTMR14 gene contains 19 exons; EST database analysis indicated that exons 17 and 18 are alternatives.
By genomic sequence analysis, Tosch et al. (2006) mapped the MTMR14 gene to chromosome 3p25.3.
Tosch et al. (2006) described 2 sporadic cases of centronuclear myopathy in which each proband carried a heterozygous missense mutation in the MTMR14 gene. The first proband and his unaffected father carried an R336Q substitution (611089.0001). A second mutant allele was postulated, but not identified. The other proband carried a Y462C substitution in MTMR14 (611089.0002) and an additional missense mutation in DYN2 (E368K; 602378.0007), consistent with autosomal dominant centronuclear myopathy (CNM1; 160150). The Y462C mutation was also found in a control individual. Both variants impaired enzymatic function, the R336Q mutation strongly and the Y462C mutation to a lesser extent. Tosch et al. (2006) remarked that myotubular myopathy patients with other characterized mutations in DYN2 usually have an age of onset in childhood or adulthood, whereas the age of onset in their patient was neonatal. The report raised the possibility of MTMR14 being a modifier of the phenotype in some cases of centronuclear myopathy.
Shen et al. (2009) found that Mtmr14-null mice had muscle weakness and increased fatigue with exercise. Isolated muscles from mutant mice showed decreased contractile force, exacerbated fatigue, and prolonged relaxation compared to muscle from wildtype mice. Mtmr14 deficiency resulted in increased elevated resting calcium levels in myotubes due to spontaneous calcium leakage from the sarcoplasmic reticulum. This leakage was attributed to decreased activity of Mtmr14 phosphatase activity and accumulation of substrates, especially PtdIns(3,5)P2 and PtdIns(3,4)P2. In addition, PtdIns(3,5)P2 and PtdIns(3,4)P2 bound to and directly activated the RYR1 (180901) calcium release channel in the sarcoplasmic reticulum. The findings indicated that fine control of PtdInsP levels in muscle cells is essential for maintaining calcium homeostasis and muscle performance.
Normal aging is associated with sarcopenia, or a decrease in muscle mass and function. Romero-Suarez et al. (2010) found that Mtmr14-null mice manifested features of sarcopenia much earlier (12 to 14 months) compared to wildtype mice (22 to 24 months). In particular, young and mature mutant mice behaved like old wildtype mice, indicating earlier onset of locomotor dysfunction in mutant mice. These changes were associated with muscle atrophy and a decrease in contractile force and power in the muscles of mutant mice. Wildtype mice showed downregulation of Mtmr14 during normal aging, and muscle tissue from both old wildtype and mutant mature mice showed dysfunctional calcium homeostasis, with increased resting calcium levels and decreased calcium release from the sarcoplasmic reticulum when triggered. The findings indicated that Mtmr14 is a potent regulator of skeletal muscle function under normal conditions and that its downregulation may contribute to age-related sarcopenia. Romero-Suarez et al. (2010) concluded that loss of Mtmr14 results in altered PtdIns(3,5)P2 signaling, as well as altered calcium signaling, which can affect a variety of cell processes.
Dowling et al. (2010) examined zebrafish MTMR14 using gene dosage manipulation. As with MTM1 (300415) knockdown, morpholino-mediated knockdown of MTMR14 resulted in morphologic abnormalities, a developmental motor phenotype characterized by diminished spontaneous contractions and abnormal escape response, and impaired excitation-contraction coupling. In contrast to MTM1 knockdown, however, muscle ultrastructure was unaffected. Double knockdown of MTM1 and MTMR14 significantly impaired motor function and altered skeletal muscle ultrastructure. The combined effect of reducing levels of both MTMR14 and MTM1 was significantly more severe than either knockdown alone, an effect which may be mediated by increased autophagy. The authors concluded that MTMR14 is required for motor function and, in combination with MTM1, is required for myocyte homeostasis and normal embryonic development.
Tosch et al. (2006) reported a 12-year old Brazilian boy with centronuclear myopathy (CNM1; 160150) who presented with neonatal hypotonia, proximal muscle weakness, and ophthalmoparesis. Both he and his clinically unaffected father were heterozygous for a 1007G-A transition in exon 11 of the MTMR14 gene. The mutation was predicted to result in an arg336-to-gln (R336Q) substitution in a highly conserved region of the active site of the protein. The mutation was not found in 820 control chromosomes. Immunoprecipitation assays detected a strong decrease in the phosphatase activity of the R336Q mutant, 22% of the level of wildtype. A second mutation in MTMR14 was not identified, and the patient did not have a mutation in exons or splice sites of the DNM2 gene (602378). Tosch et al. (2006) hypothesized that another mutant allele in either the MTMR14 gene or in another gene must be present.
Tosch et al. (2006) reported a 36-year-old woman with centronuclear myopathy-1 (CNM1; 160150) caused by a heterozygous missense mutation in the DNM2 gene (E368K; 602378.0007) who also carried a heterozygous 1385A-G transition in exon 16 of the MTMR14 gene, resulting in a tyr462-to-cys (Y462C) substitution in a semiconserved region outside of the active site of the protein. The Y462C mutation was found in 1 of 700 Brazilian control chromosomes. The Y462C mutant displayed 80% of the phosphatase activity of the wildtype protein in immunoprecipitation assays. Both mutations occurred de novo. The patient presented with neonatal hypotonia, muscle weakness, and ophthalmoparesis. The report raised the possibility of MTMR14 being a modifier of the phenotype in some cases of centronuclear myopathy.
Dowling, J. J., Low, S. E., Busta, A. S., Feldman, E. L. Zebrafish MTMR14 is required for excitation-contraction coupling, developmental motor function and the regulation of autophagy. Hum. Molec. Genet. 19: 2668-2681, 2010. [PubMed: 20400459] [Full Text: https://doi.org/10.1093/hmg/ddq153]
Romero-Suarez, S., Shen, J., Brotto, L., Hall, T., Mo, C., Valdivia, H. H., Andresen, J., Wacker, M., Nosek, T. M., Qu, C.-K., Brotto, M. Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis. Aging 2: 504-513, 2010. [PubMed: 20817957] [Full Text: https://doi.org/10.18632/aging.100190]
Shen, J., Yu, W.-M., Brotto, M., Scherman, J. A., Guo, C., Stoddard, C., Nosek, T. M., Valdivia, H. H., Qu, C.-K. Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca(2+) homeostasis. Nature Cell Biol. 11: 769-776, 2009. [PubMed: 19465920] [Full Text: https://doi.org/10.1038/ncb1884]
Tosch, V., Rohde, H. M., Tronchere, H., Zanoteli, E., Monroy, N., Kretz, C., Dondaine, N., Payrastre, B., Mandel, J.-L., Laporte, J. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum. Molec. Genet. 15: 3098-3106, 2006. [PubMed: 17008356] [Full Text: https://doi.org/10.1093/hmg/ddl250]