HEXA – GM2 gangliosidosis

HEXA encodes the α-subunit of β-hexosaminidase A, a lysosomal enzyme responsible for GM2 ganglioside catabolism. Biallelic pathogenic variants in HEXA underlie autosomal recessive GM2 gangliosidosis, encompassing Tay-Sachs disease and chronic/juvenile variants. The clinical spectrum ranges from infantile-onset neurodegeneration with hypotonia and cherry-red spots to adult-onset motor neuron involvement.

Genetic evidence includes over 73 UK-reported GM2 gangliosidosis cases (PMID:22115551) with diverse variant classes. Missense alleles such as c.1510C>T (p.Arg504Cys) in compound heterozygosity with p.Gly269Ser have been identified in chronic GM2 patients (PMID:1827944). Recurrent Ashkenazi Jewish mutations like c.805G>A (p.Gly269Ser) are observed homozygously or in compound heterozygosity (PMID:1840100). Frameshift and splice-site variants expand the allelic spectrum in multiple populations.

Segregation analysis across pedigrees confirms autosomal recessive transmission: the p.Arg504Cys/p.Gly269Ser genotype segregated with chronic GM2 phenotypes in siblings (PMID:1827944), and juvenile-onset spinal muscular atrophy presentations further support familial concordance (PMID:7898712).

Functional assays demonstrate that pathogenic α-subunit substitutions impair dimerization, abrogate HexA activity, and trigger endoplasmic reticulum-associated degradation. Site-directed mutants secreted as monomers lack catalytic activity in COS-1 cells (PMID:1827944), and misfolded variants such as p.Gly269Ser and p.Glu482Lys undergo proteasomal clearance (PMID:27682588).

Common pseudodeficiency alleles c.739C>T (p.Arg247Trp) and c.745C>T (p.Arg249Trp) reduce synthetic substrate activity without clinical disease, accounting for ~32% of non-Jewish carriers and complicating biochemical screening (PMID:1384323; PMID:7902672). DNA-based analyses are essential for accurate carrier detection.

Integration of genetic and experimental data supports a definitive gene-disease relationship. HEXA mutation analysis enables early diagnosis, carrier screening, and informed counseling. Comprehensive sequencing with functional validation is critical for clinical decision-making and future therapeutic development.

References

• Developmental medicine and child neurology • 2012 • GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed. PMID:22115551
• American journal of human genetics • 1991 • A third mutation at the CpG dinucleotide of codon 504 and a silent mutation at codon 506 of the HEX A gene. PMID:1827944
• Developmental neuroscience • 1991 • Molecular and clinical heterogeneity of adult GM2 gangliosidosis. PMID:1840100
• Neurology • 1995 • A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype. PMID:7898712
• Molecular biology of the cell • 2016 • Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation. PMID:27682588
• American journal of human genetics • 1992 • A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening. PMID:1384323
• American journal of human genetics • 1993 • A second mutation associated with apparent beta-hexosaminidase A pseudodeficiency: identification and frequency estimation. PMID:7902672

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