ClinGen Dosage Sensitivity Curation Page

MAGT1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21796205 Li et al. 2011: Describes two young brothers with the XMEN phenotype (X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia). A 10 bp deletion was found in MAGT1 in both brothers. The deletion removes a splice donor site located in the 3? exon-intron junction of exon 7, and was present in the unaffected mother, grandmother, and great-grandmother of the patients. The mother was shown to have skewed X-inactivation. The patients? mutant MAGT1 splice variant was ~150 bp smaller than the mother?s normal splice variant of approximately 1100 bases and missing both exon 7 and 8, leading to a premature stop codon. Apparent nonsense-mediated decay caused markedly decreased mRNA expression. The MagT1 protein was undetectable in the patient cells by Western blot or immunofluorescent cell surface staining. Another unrelated, similarly affected patient was found to have a nonsense mutation in exon 3 of MAGT1 (R137X), leading to a 90% decrease in mRNA expression.

Haploinsufficiency phenotype comments:

Variation in MAGT1 has also been reported in association with intellectual disability in the context of congenital disorders of glycosylation. Molinari et al. (2008) (PMID: 18455129) report a 932T-G transversion in exon 9 of the MAGT1 gene, resulting in a val311-to-gly (V311G) substitution in a conserved residue. There were 2 girls with mild intellectual disability, and 2 boys with severe intellectual disability. The 2 affected males had a similar phenotype with a similar degree of impairment. Their mother was described as "slow" and was found to carry the mutation. One affected sister was said to be affected more mildly than the brothers. The mutation was not identified in 267 control chromosomes, and MAGT1 mRNA was not detected in patient lymphoblastoid cell lines.

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

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.