MTM1 – X-linked Myotubular Myopathy

X-linked myotubular myopathy (XLMTM; MONDO:0010683) is a severe congenital myopathy caused by pathogenic variants in MTM1 (HGNC:7448), which encodes the lipid phosphatase myotubularin. Affected male infants present with profound hypotonia, generalized muscle weakness, and respiratory insufficiency, often leading to early mortality. Female carriers are typically asymptomatic but can manifest variable symptoms due to skewed X-inactivation or germline mosaicism ([PMID:10466421]; [PMID:32805447]).

Inheritance of XLMTM is X-linked recessive, with most male patients hemizygous for MTM1 variants. Segregation studies demonstrate variant transmission in multiple families, including reports of germline mosaicism and paternal transmission, underscoring importance for genetic counseling ([PMID:10466421]; [PMID:28622964]).

Over 250 pathogenic MTM1 variants have been described in more than 300 unrelated families, spanning missense, nonsense, frameshift, splice-site, deep intronic, and structural rearrangements. Recurrent variants such as c.1132G>C (p.Gly378Arg) and c.1262G>A (p.Arg421Gln) illustrate hotspots within the phosphatase domain. The broad mutational spectrum correlates with phenotypic variability from lethal neonatal forms to mild, late-onset presentations ([PMID:12522554]; [PMID:9305655]).

Functional assays confirm that MTM1 loss-of-function underlies XLMTM, with deficient dephosphorylation of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. Overexpression of wild-type myotubularin in patient cells restores lipid metabolism, whereas catalytically inactive mutants fail to do so, linking enzymatic activity to disease pathogenesis ([PMID:14660569]).

Animal models further substantiate causality: Mtm1 knockout mice recapitulate human pathology, including myofiber atrophy and central nuclei. Rescue experiments using adeno-associated virus–mediated MTM1 expression, including phosphatase-dead variants, ameliorate histological and functional deficits, demonstrating both catalytic and structural roles of myotubularin ([PMID:22068590]; [PMID:23071445]).

Integration of these data supports a definitive gene–disease association. Genetic testing for MTM1 variants is essential for diagnosis, carrier detection, and prenatal evaluation. Emerging therapies targeting downstream interactors (e.g., BIN1, DNM2) offer promise for modifying disease course. Key take-home: MTM1 genetic analysis coupled with functional and animal studies provides a robust framework for diagnosis and therapeutic development in XLMTM.

References

• Clinical genetics • 1999 • Germline mosaicism in X-linked myotubular myopathy. PMID:10466421
• Human genetics • 2003 • Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. PMID:12522554
• Human molecular genetics • 1997 • Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. PMID:9305655
• The Journal of biological chemistry • 2004 • Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells. PMID:14660569
• Human molecular genetics • 2012 • Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype. PMID:22068590
• PLoS genetics • 2012 • Phosphatase-dead myotubularin ameliorates X-linked centronuclear myopathy phenotypes in mice. PMID:23071445

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