GM2A – Tay-Sachs Disease AB Variant

GM2A encodes the GM2 activator protein (GM2AP), a critical cofactor for lysosomal β-hexosaminidase A–mediated degradation of GM2 ganglioside. Deficiency of GM2AP gives rise to the AB variant of GM2 gangliosidosis (Tay-Sachs disease AB variant; MONDO:0010099), an autosomal recessive neurodegenerative disorder characterized by GM2 accumulation in neurons and clinical features indistinguishable from classic Tay-Sachs disease.

Molecular confirmation has been reported in eight unrelated patients with biallelic GM2A mutations. Variant classes include premature stop codons (e.g., c.160G>T (p.Glu54Ter))(PMID:26082327), frameshift deletions, exon‐level deletions(PMID:28540636), and missense substitutions such as c.164C>T (p.Pro55Leu) and c.259G>T (p.Glu87Ter)(PMID:28417072). These findings expand the GM2A variant spectrum associated with the AB phenotype.

Segregation analysis in one Turkish family identified an additional affected sibling carrying a novel homozygous GM2A variant(PMID:33819415). No consanguinity was reported in several pedigrees, indicating independent allelic occurrences. Overall, there is evidence for one additional segregant across reported families.

Functional studies corroborate the loss-of-function mechanism. Expression of mutant Arg169Pro in BHK cells yielded undetectable GM2AP by Western blot(PMID:8244332). Patient fibroblasts from compound heterozygotes lacked GM2AP and showed impaired GM2 catabolism by immunohistochemical and metabolic‐labeling assays(PMID:28417072). Site‐directed variants in the enzyme‐binding helix (D113K, M117V, E123K) retained lipid binding but lost capacity to stimulate HexA-mediated GM2 degradation, delineating the critical interface(PMID:16478472).

The pathogenic mechanism is consistent with loss of GM2AP function—either via premature degradation or disrupted enzyme interaction—resulting in lysosomal GM2 accumulation. These data support comprehensive diagnostic evaluation of GM2A, including sequencing and exon‐level copy‐number assessment, in patients with characteristic neurological signs and cherry-red spots but normal hexosaminidase enzyme activities.

Collectively, GM2A meets ClinGen criteria for a Moderate gene–disease association, with Moderate genetic evidence and Strong functional evidence. Key take-home: GM2A deficiency is a confirmed autosomal recessive cause of AB variant GM2 gangliosidosis, and targeted molecular and functional testing is essential for accurate diagnosis and genetic counseling.

References

• JIMD reports • 2016 • GM2-Gangliosidosis, AB Variant: Clinical, Ophthalmological, MRI, and Molecular Findings. PMID:26082327
• Molecular genetics and metabolism reports • 2017 • Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G>T and c.164C>T mutations in the GM2A gene. PMID:28417072
• JIMD reports • 2018 • GM2 Activator Deficiency Caused by a Homozygous Exon 2 Deletion in GM2A. PMID:28540636
• Journal of pediatric endocrinology & metabolism : JPEM • 2021 • Two patients from Turkey with a novel variant in the GM2A gene and review of the literature. PMID:33819415
• Human genetics • 1993 • Molecular genetics of GM2-gangliosidosis AB variant: a novel mutation and expression in BHK cells. PMID:8244332
• The FEBS journal • 2006 • The enzyme-binding region of human GM2-activator protein. PMID:16478472

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