OMIA 001461-9615 : Gangliosidosis, GM2, type I (B variant) in Canis lupus familiaris

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

Possibly relevant human trait(s) and/or gene(s) (MIM number): 272800

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 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:

Symbol Description Species Chr Location OMIA gene details page Other Links
HEXA hexosaminidase A (alpha polypeptide) Canis lupus familiaris 30 NC_006612.3 (35862525..35836788) HEXA Homologene, Ensembl, NCBI gene


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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Japanese Chin dog Gangliosidosis, GM2, type I (B variant) HEXA missense c.967G>A p.E323K 2013 23266199
Japanese Chin dog Gangliosidosis, GM2, type I HEXA missense CanFam3.1 30 g.35841247G>A c.967G>A p.E323K 2013 23266199 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2016 Lawson, C.A., Martin, D.R. :
Animal models of GM2 gangliosidosis: utility and limitations. Appl Clin Genet 9:111-20, 2016. Pubmed reference: 27499644. DOI: 10.2147/TACG.S85354.
2013 Freeman, A.C., Platt, S.R., Vandenberg, M., Holmes, S., Kent, M., Rech, R., Howerth, E., Mishra, S., O'Brien, D.P., Wenger, D. :
GM2 gangliosidosis (B variant) in two Japanese Chins: clinical, magnetic resonance imaging and pathological characteristics. J Vet Intern Med 27:771-6, 2013. Pubmed reference: 23731274. DOI: 10.1111/jvim.12118.
Sanders, D.N., Zeng, R., Wenger, D.A., Johnson, G.S., Johnson, G.C., Decker, J.E., Katz, M.L., Platt, S.R., O'Brien, D.P. :
GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: a potential model for Tay Sachs disease. Mol Genet Metab 108:70-5, 2013. Pubmed reference: 23266199. DOI: 10.1016/j.ymgme.2012.11.008.
1985 Cummings, JF., Wood, PA., Walkley, SU., de Lahunta, A., DeForest, ME. :
GM2 gangliosidosis in a Japanese spaniel. Acta Neuropathol (Berl) 67:247-53, 1985. Pubmed reference: 2931941.

Edit History

  • Created by Tosso Leeb on 25 May 2013
  • Changed by Tosso Leeb on 25 May 2013
  • Changed by Frank Nicholas on 25 May 2013
  • Changed by Frank Nicholas on 26 Feb 2014