ClinGen Dosage Sensitivity Curation Page

MTM1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10790201 Laporte et al 2000 reported 29 variants in novel cases, including 16 variants not described before. Among these, 14 are clearly deleterious mutations that predict a truncated protein (nonsense and frameshift). Three changes affect essential nucleotides for the donor splice site, and the common FIQ420-421ins was found in two patients. To date, 198 variants have been identified in unrelated families, accounting for 133 different disease-associated variants which are widespread throughout the MTM1 gene. Most single-nucleotide variants are truncating, while 26% (35/133) are missense variants affecting residues conserved in the Drosophila ortholog and in the homologous MTMR1 gene. While most truncating mutations cause the severe and early lethal phenotype, some missense mutations are associated with milder forms and prolonged survival (up to 54 years).
11793470 Herman et al 2002 reported variants detected in 50 additional U.S. families with biopsy-proven MTM1. Forty-one of the patients have not been described previously, including 18 with novel mutations. 88% of the mothers of sporadic cases that were studied were identified as carriers, extending the previously reported high-carrier frequency for this disorder. Among the variants detected, 16 were missense, 9 were nonsense, 12 were splicing variants, 10 were small deletion/insertions, and 3 were large deletions.
12522554 Biancalana et al 2003 reported additional variants of MTM1 in 77 patients, including 35 novel ones.

Haploinsufficiency phenotype comments:

Loss of function mutations in MTM1 cause X-linked myotubular myopathy, including frameshift, nonsense, splicing, and deletion mutations. 7% of all variants are deletions involving one or more exons and typically cause severe disease. Males are always affected. Female carriers are usually asymptomatic but there have been rare reports of symptomatic females due to skewed X-inactivation. PMID: 10790201, 11793470, 12522554, 15145343, 15725586. See Gene Reviews.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There are a couple of publications about the duplication of a part of MTM1 is also causing X-linked myotubular myopathy, but they didn?t encompass the whole gene (PMID 22968136, 22153990). One case report described a patient with a duplication almost cover the whole MTM1 gene, but it also harbors another gene, MAMLD1 (PMID 23273872).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.