• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
MAGT1 (HGNC:28880) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
magnesium transporter 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
DKFZp564K142, IAP, OST3B, MRX95, SLC58A1
%HI
34.31(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.96(Read more about gnomAD pLI score)
LOEUF
0.33(Read more about gnomAD LOEUF score)
Cytoband
Xq21.1
Genomic Coordinates
GRCh37/hg19: chrX:77081244-77151065 NCBI Ensembl UCSC
GRCh38/hg38: chrX:77825747-77895568 NCBI Ensembl UCSC
MANE Select Transcript
NM_001367916.1 ENST00000618282.5 (Read more about MANE Select)
Function
Accessory component of the STT3B-containing form of the N- oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains (PubMed:31831667). Involved in N- glycosylation of STT3B-dependent substrates (PubMed:31831667). Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residu... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-36300
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
09/22/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • X-linked immunodeficiency with magnesium defect, EBV infection and neoplasia (XMEN) Monarch
HI Evidence:
  • PUBMED: 21796205
    Li et al. 2011 described two young brothers with the XMEN phenotype (X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia). Using methylation-sensitive restriction endonuclease HpaII, the authors sequenced mother's methylated X-chromosome DNA and identified a 10 bp deletion in the MAGT1 gene. The deletion was also identified in both brothers. It 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 completely skewed lyonization with only the X chromosome inherited by her two sons inactivated in her T cells. 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's cells by Western blot or immunofluorescent cell surface staining. Another unrelated and similarly affected patient was found to have a nonsense variant in exon 3 of MAGT1 (R137X), leading to a 90% decrease in mRNA expression. The authors did not describe maternal carrier status in this case. None of the individuals reported in this paper had intellectual disability.
  • PUBMED: 23846901
    Chaigne-Delalande et al., 2013 described four patients with novel MAGT1 LoF variants (p.Trp37*, p.Arg137*, p.Arg200Glyfs*13 and p.Asn287*fs*1) and Li et al. 2011 (PMID: 21796205) patients to understand defective imune response against Epstein-Barr virus (EBV). All carrier mothers were unaffected and male carriers had recurent infections. Three of the four novel patients had lymphomas before adulthood as B-cell lymphoproliferative disorders, Burkitt’s lymphoma and Hodgkin’s lymphoma. The authors demonstrated magnesium supplementation restored EBV specific cytotoxic functions in XMEN disease patients cells by invitro assays. All patients had normal adaptive immune responses, generating EBV-specific memory CD8+ T-cells. None of the individuals reported in this paper had intellectual disability.
  • PUBMED: 24550228
    Li et al., 2014 reviewed XMEN disease and included Li et al., 2011 (PMID: 21796205) and Chaigne-Delalande et al., 2013 (PMID: 23846901) patients in this article. XMEN disease patients had persistent high EBV levels, inverted CD4:CD8 ratio and they developed various EBV-associated B-cell lymphoproliferative disorders after puberty. Other variable imune-related symptons were also observed and described in this review. According to the authors, the mothers of XMEN disease patients have preferential X chromosome inactivation of the chromosome harboring the mutant allele and appear to be asymptomatic. MAGT1 pathogenic variants associated with XMEN disease lead to premature translational termination with loss of mRNA expression and subsequent nonsense-mediated decay. Mechanisms of pathogenesis, diagnostic, therapeutics and future considerations were also discussed by the authors.
  • PUBMED: 25504528
    Dhalla et al., 2014 is a case report describing a 58 year old patient with XMEN disease diagnosed at age 36 years old after a referral to immunology. At age of 52, the patient exhibited increased respiratory tract infections, high EBV viremia, lymphadenopathy, hepatosplenomegaly and B-symptoms. At age of 57, the patient died as the result of lymphoproliferative disease and progressive multifocal leucoencephalopathy. The patient had five brothers and four sisters reported to be healthy with no history suggestive of primary immune deficiency or lymphoma. One of his sister had a son who developed an EBV lymphoproliferative disease at the age of 13 years. After genetic investigation, both patient and his nephew were identified with a novel LoF MAGT1 variant, p.R238X; the proband's sister (affected nephew's mother) was not tested. None of the individuals reported in this paper had intellectual disability.
  • PUBMED: 31714901
    Ravell et al., 2020 reviewed the records of 23 patients from 17 unrelated families with XMEN disease and loss of function (LoF) MAGT1 variants. They reported 14 unique variants including putative LoF missense variants, all of them only affecting males. The most consistent diagnostic finding was decreased NKG2D surface expression on both CD8+ T cells and NK cells, which causes EBV infection susceptibility. Other frequently reported diagnoses were mild thrombocytopenia, transient neutropenia, sometimes associated with mouth sores, and antibody-mediated cytopenias. The authors presented substantial functional data, molecular and cellular mechanisms. The authors did not find intellectual disability or dysmorphic features in their cohort of patients.
  • PUBMED: 32451662
    Ravell et al., 2020 reviewed the literature and reported 18 unique LoF MAGT1 variants associated with XMEN disease. A total of 36 unique male patients have been reported. Females with heterozygous MAGT1 variants are healthy carriers with a pattern of X chromosome inactivation skewed toward the normal allele in their hematopoietic cells. Molecular mechanisms and detailed clinical features were reported and discussed by the authors. Cancer predisposition, liver diseases and neurological abnormalities in XMEN disease patients were also featured in this review. The authors reviewed and discussed the association of MAGT1 with intellectual disability. Considering all available scientific evidences, the authors suggested that MAGT1 loss of function alone is unlikely to cause intellectual disability.
HI Evidence Comments:
Variants in MAGT1 gene have been associated wtih XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia). Historically, variants in MAGT1 have also been proposed to be involved with intellectual disability; however, Piton et al 2013 (PMID: 23871722) have disputed these claims. According to the literature, the vast majority of patients with MAGT1 LoF variants do not have intellectual disability (PMIDs 21983175; 24550228; 25205404; 25313976; 25504528; 25956530; 26422833).
NOTE:

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 (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
NOTE:

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.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)