MGAT2 – Congenital Disorder of Glycosylation

MGAT2 has been robustly associated with congenital disorder of glycosylation, a multisystemic disorder characterized by abnormal glycoprotein synthesis. The evidence supports an autosomal recessive inheritance pattern with causative mutations leading to a near total loss of enzyme function. Multiple independent studies have identified pathogenic variants in patients, with at least two unrelated probands reported (PMID:8808595) and additional cases noted in cohort studies (PMID:28742265) and systematic reviews (PMID:31420886).

Segregation analyses further reinforce the association; in one study, sequencing of the MGAT2 coding region in a patient’s extended family (23 relatives, PMID:8808595) showed that the identified variants co‐segregated with disease status. One representative and well‐characterized variant is c.869C>T (p.Ser290Phe), which has been reported in affected individuals.

The genetic evidence is supplemented by compelling functional data. Experimental assessments in patient fibroblasts and animal models demonstrate that these mutations result in over 98% reduction in GnT II enzyme activity. The loss of function observed in vitro (PMID:8808595) and the recapitulation of key disease features in Mgat2-null mice (PMID:11805078, PMID:12417412) confirm that impaired glycosylation is central to the disease mechanism.

Further, systematic reviews and epidemiological studies have identified additional CDG patients with MGAT2 mutations. Although these studies often include several genes causing CDG phenotypes, the recurrent identification of MGAT2 variants in affected individuals underscores the overall pathogenic role of this gene in congenital disorders of glycosylation (PMID:28742265, PMID:31420886).

No significant conflicting evidence has been reported; however, the phenotypic spectrum shows some variability, likely reflecting allele-specific effects and genetic background differences among patients. The convergence of clinical, genetic, and functional data permits a high degree of confidence in the diagnostic and therapeutic relevance of MGAT2 in CDG.

Key take‑home message: Integrated data from case reports, segregation studies, and functional assays establish MGAT2 as a critical gene in congenital disorder of glycosylation, supporting its robust utility in clinical diagnostics and management.

References

• Biochimica et biophysica acta • 1999 • Carbohydrate-deficient glycoprotein syndrome type II PMID:10571011
• American journal of human genetics • 1996 • Mutations in MGAT2 causing CDG type II with reduced GnT II activity PMID:8808595
• American journal of medical genetics. Part A • 2017 • Congenital disorders of glycosylation: The Saudi experience PMID:28742265
• Glycobiology • 2001 • Modeling human congenital disorder of glycosylation type IIa in the mouse PMID:11805078
• Journal of inherited metabolic disease • 2020 • Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review PMID:31420886

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