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J Vet Intern Med. 2017 Sep;31(5):1520-1526. doi: 10.1111/jvim.14794. Epub 2017 Aug 20.

GM2 Gangliosidosis in Shiba Inu Dogs with an In-Frame Deletion in HEXB.

Author information

1
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO.
2
Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO.
3
Department of Neurology, Jefferson Medical College, Philadelphia, PA.
4
Pittsburgh Veterinary Specialty and Emergency Center, Pittsburgh, PA.
5
Veterinary Specialty and Emergency Center, Blue Pearl Veterinary Partners, Levittown, PA.
6
Division of Animal Sciences, University of Missouri, Columbia, MO.
7
Division of Animal Sciences and Informatics Institute, University of Missouri, Columbia, MO.
8
Mason Eye Institute, University of Missouri, Columbia, MO.

Abstract

Consistent with a tentative diagnosis of neuronal ceroid lipofuscinosis (NCL), autofluorescent cytoplasmic storage bodies were found in neurons from the brains of 2 related Shiba Inu dogs with a young-adult onset, progressive neurodegenerative disease. Unexpectedly, no potentially causal NCL-related variants were identified in a whole-genome sequence generated with DNA from 1 of the affected dogs. Instead, the whole-genome sequence contained a homozygous 3 base pair (bp) deletion in a coding region of HEXB. The other affected dog also was homozygous for this 3-bp deletion. Mutations in the human HEXB ortholog cause Sandhoff disease, a type of GM2 gangliosidosis. Thin-layer chromatography confirmed that GM2 ganglioside had accumulated in an affected Shiba Inu brain. Enzymatic analysis confirmed that the GM2 gangliosidosis resulted from a deficiency in the HEXB encoded protein and not from a deficiency in products from HEXA or GM2A, which are known alternative causes of GM2 gangliosidosis. We conclude that the homozygous 3-bp deletion in HEXB is the likely cause of the Shiba Inu neurodegenerative disease and that whole-genome sequencing can lead to the early identification of potentially disease-causing DNA variants thereby refocusing subsequent diagnostic analyses toward confirming or refuting candidate variant causality.

KEYWORDS:

Autofluorescent storage bodies; Lysosomal storage disease; Neuronal ceroid lipofuscinosis; Sandhoff disease; Whole-genome sequence

PMID:
28833537
PMCID:
PMC5598891
DOI:
10.1111/jvim.14794
[Indexed for MEDLINE]
Free PMC Article

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