A frameshift mutation in the canine HEXB gene in toy poodles with GM2 gangliosidosis variant 0 (Sandhoff disease)

Rahman, Mohammad Mahbubur; Chang, Hye-Sook; Mizukami, Keijiro; Hossain, Mohammad Alamgir; Yabuki, Akira; Tamura, Shozo; Kitagawa, Masato; Mitani, Sawane; Higo, Tomoya; Uddin, Mohammad M.; Uchida, Kazuyuki; Yamato, Osamu

doi:10.1016/j.tvjl.2012.05.021

Cited by 18 publications

(31 citation statements)

References 19 publications

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“…In an affected Golden Retriever and in affected members of a Toy Poodle family, marked reductions of β-hexosaminidase activity measured with both MUG and MUGS suggested that these dogs have canine version of the human 0 variant or Sandhoff disease, which is caused by mutations in HEXB [20,22,28], and the causal mutation in HEXB has been identified in the poodles [29]. On the other hand, β-hexosaminidase activities in samples from German Shorthaired Pointers and a mixed breed dog with GM2 gangliosidosis showed normal to elevated hexosaminidase activity with MUG and decreased activity in the German Shorthaired Pointers when assayed with the MUGS substrate [18,19,30].…”

Section: Discussionmentioning

confidence: 99%

GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: A potential model for Tay Sachs disease

Sanders

Zeng

Wenger

et al. 2013

Molecular Genetics and Metabolism

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Section: Discussionmentioning

confidence: 99%

GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: A potential model for Tay Sachs disease

Sanders

Zeng

Wenger

et al. 2013

Molecular Genetics and Metabolism

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“…The diseases are inherited in an autosomal recessive manner, and affected individuals die prematurely due to brain damage, with progressive neurological signs, including motor and psychointellectual dysfunction and visual defects. In veterinary species, naturally occurring GM2 gangliosidoses have been shown in dogs, cats, sheep, pigs, deer and flamingos [4, 11]. …”

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confidence: 99%

“…The clinical signs of SD in toy poodles include motor disorders and tremor starting between 9 and 12 months of age and death resulting from progressive neurological deterioration between 18 and 23 months of age. The causative mutation of SD in toy poodles has been identified as a homozygous single base pair (bp) deletion of guanine in exon 3 at nucleotide position 283 of the putative open reading frame of the canine HEXB gene (c.283delG), allowing antemortem molecular diagnosis by using a conventional PCR-based DNA test [11]. …”

mentioning

confidence: 99%

“…A post-mortem liver specimen was collected from a toy poodle with SD, and the genomic DNA was isolated using a commercial kit (QIAamp DNA Micro Kit, Qiagen, Valencia, CA, U.S.A.), in accordance with the manufacturer’s protocol. Whole blood or saliva samples spotted onto the Flinders Technology Associates filter paper (FTA card, Whatman International, Piscataway, NJ, U.S.A.) were collected from two affected, four heterozygous carrier and five wild-type toy poodles, genotypes of which were determined previously using direct sequencing analysis [11]. In addition, whole blood or saliva samples were collected from 496 toy poodles for an epidemiological survey.…”

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confidence: 99%

“…The ancestry in North America was traced using pedigree information provided by the Poodle Pedigree Database (http://www.poodlepedigree.com). The pedigree data of toy poodles with SD were updated based on the previous data [11, 12] and the newly found information in the present study.…”

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confidence: 99%

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Real-Time PCR Genotyping Assay for GM2 Gangliosidosis Variant 0 in Toy Poodles and the Mutant Allele Frequency in Japan

et al. 2014

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GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the HEXB gene. In canine SD, a pathogenic mutation (c.283delG) of the canine HEXB gene has been identified in toy poodles. In the present study, a TaqMan probe-based real-time PCR genotyping assay was developed and evaluated for rapid and large-scale genotyping and screening for this mutation. Furthermore, a genotyping survey was carried out in a population of toy poodles in Japan to determine the current mutant allele frequency. The real-time PCR assay clearly showed all genotypes of canine SD. The assay was suitable for large-scale survey as well as diagnosis, because of its high throughput and rapidity. The genotyping survey demonstrated a carrier frequency of 0.2%, suggesting that the current mutant allele frequency is low in Japan. However, there may be population stratification in different places, because of the founder effect by some carriers. Therefore, this new assay will be useful for the prevention and control of SD in toy poodles.

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Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

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Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β‐Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb−/−) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb−/− zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb−/−) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non‐neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo.

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A frameshift mutation in the canine HEXB gene in toy poodles with GM2 gangliosidosis variant 0 (Sandhoff disease)

Cited by 18 publications

References 19 publications

GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: A potential model for Tay Sachs disease

GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: A potential model for Tay Sachs disease

Real-Time PCR Genotyping Assay for GM2 Gangliosidosis Variant 0 in Toy Poodles and the Mutant Allele Frequency in Japan

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

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