In other species: muntjak , American flamingo , sheep , rabbit , pig

Categories: Lysosomal storage disease

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 272800 (trait) , 606869 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: Tay-Sachs disease

Species-specific name: Gangliosidosis, GM2, type I

Species-specific symbol: GM2

Species-specific description: GM2 gangliosidos is a fatal lysosomal storage disease caused by a deficiency of β-hexosaminidase (EC 3.2.1.52). There are two major isoforms of the enzyme: hexosaminidase A composed of an α and a β subunit (encoded by HEXA and HEXB genes, respectively); and, hexosaminidase B composed of two β subunits. Hexosaminidase A requires an activator protein encoded by GM2A to catabolize GM2 ganglioside, but even in the absence of the activator protein, it can hydrolyze the synthetic substrates commonly used to assess enzyme activity. Mutations in the HEXA gene cause type I (or "type B") GM2 gangliosidosis, also called Tay-Sachs disease in humans. In dogs the age of onset is between 1 and 2 years and affected dogs exhibit progressive cerebellar ataxia, altered mental status and vision deficits. The disease is progressive and leads to death or requires euthanasia within a few months.

History: In 1985 a GM2 gangliosidosis in Japanese Spaniels or Japanese Chin dogs was described clinically and histopathologically (Cummings et al. 1985). Recently, two new cases were carefully diganosed clinically and histopathologically. The biochemical analysis of the storage material clearly indicated a GM2 gangliosidosis. The sequence analysis of the candidate gene HEXA revealed a highly plausible candidate causative mutation, which was perfectly associated with the phenotype (Sanders et al. 2013)

Mapping: The causative variant was identified by a candidate gene approach.

Molecular basis: GM2 gangliosidosis, type I in Japanese Chin dogs is most likely caused by the c.967G>A variant in the HEXA gene, which leads to the p.E323K substitution. The wildtype glutamate at position 323 is part of the catalytically active site of hexosaminidase, Therefore, the variant is predicted to result in a complete loss of enzymatic activity (Sanders et al. 2013). Genotyping one of the two cases in this same breed for the c.967G>A variant provided supporting evidence for the causality of this variant (Freeman et al., 2013).

Pathology: Freeman et al. (2013) reported " the first MRI description of the B variant of GM2 gangliosidosis in 2 Japanese Chin dogs".

Breed: Japanese Chin dog.

Associated gene: