<scp>GM</scp>2 Gangliosidosis in Shiba Inu Dogs with an In‐Frame Deletion in <i><scp>HEXB</scp></i>

Kolicheski, Ana; Johnson, Gary S.; Villani, N.A.; O’Brien, Dennis P.; Mhlanga-Mutangadura, Tendai; Wenger, David A.; Mikoloski, K.; Eagleson, J.S.; Taylor, Jeremy F.; Schnabel, Robert D.; Katz, Martin L.

doi:10.1111/jvim.14794

Cited by 16 publications

(16 citation statements)

References 35 publications

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“…In some cases this will lead to identification of the disease-causing mutation in a non-NCL gene. For example, this is how we found a mutation in HEXB that results in NCL-like clinical signs and histopathology in Shiba Inus suffering from the canine equivalent of Sandhoff disease (Kolicheski et al, 2017b). …”

Section: Identifying the Genetic Basis For Candidate Canine Nclsmentioning

confidence: 87%

“…In addition, we evaluated Shiba Inu dogs that exhibited a progressive neurological disease and massive accumulation of autofluorescent storage material in brain, retina and heart similar to confirmed canine NCLs (Figs. 1 and 2) (Kolicheski et al, 2017b). Although the ultrastructural appearances of the storage material in brain and retina were somewhat similar to those of other canine NCLs (Ashwini et al, 2016; Gilliam et al, 2015; Guo et al, 2014; Guo et al, 2015; Katz et al, 2011; Kolicheski et al, 2017a; Kolicheski et al, 2016; Kolicheski et al, 2017b; Sanders et al, 2010), the histological appearance of the storage material in the affected Shiba Inu heart was quite distinct from that of other NCLs in which heart histopathology had been examined (Figs.…”

Section: Introduction: Neuronal Ceroid Lipofuscinoses In Humans Anmentioning

confidence: 99%

“…This suggested that the Shiba Inu disease was either a previously undescribed form of canine NCL or a phenotypically similar disease. Indeed, whole genome sequence (WGS) analysis indicated that the disease did not result from a mutation in any of the known NCL genes but rather from a mutation in HEXB (Kolicheski et al, 2017b). Mutations in the human ortholog of this gene cause Sandhoff disease, a form of gangliosidosis, so on the basis of the molecular genetic analyses the Shiba Inu disease could be excluded as a form of NCL.…”

Section: Introduction: Neuronal Ceroid Lipofuscinoses In Humans Anmentioning

confidence: 99%

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Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Katz

Rustad²,

Robinson

et al. 2017

Neurobiology of Disease

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The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from. At present, an effective treatment is available for only one form of NCL. Evidence of NCL has been documented in over 20 canine breeds and in mixed-breed dogs. To date, 12 mutations in 8 different genes orthologous to the human NCL genes have been found to underlie NCL in a variety of dog breeds. A Dachshund model with a null mutation in one of these genes is being utilized to investigate potential therapeutic interventions, including enzyme replacement and gene therapies. Demonstration of the efficacy of enzyme replacement therapy in this model led to successful completion of human clinical trials of this treatment. Further research into the other canine NCLs, with in-depth characterization and understanding of the disease processes, will likely lead to the development of successful therapeutic interventions for additional forms of NCL, for both human patients and animals with these disorders.

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Section: Identifying the Genetic Basis For Candidate Canine Nclsmentioning

confidence: 87%

Section: Introduction: Neuronal Ceroid Lipofuscinoses In Humans Anmentioning

confidence: 99%

Section: Introduction: Neuronal Ceroid Lipofuscinoses In Humans Anmentioning

confidence: 99%

See 1 more Smart Citation

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Katz

Rustad²,

Robinson

et al. 2017

Neurobiology of Disease

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“…Remarkably, natural occurring HEXB or HEXA variants leading to gangliosidoses, have been observed in various domesticated as well as wild vertebrate species including dogs, cats, sheep, Muntjak deer, and flamingos (Cork et al, ; Kanae et al, ; Kolicheski et al, ; Martin et al, ; Rahman et al, ; Torres et al, ; Zeng et al, ). The disease course in these animals is similar to that in humans, showing the conserved importance of proper processing of gangliosides.…”

Section: Introductionmentioning

confidence: 99%

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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“…Therefore, DNA testing for both GM1‐ and GM2‐gangliosidosis should be used to make a definitive diagnosis in suspicious cases and to guide breeding decisions. In addition, another report recently was published describing 2 Shiba Inus with GM2‐gangliosidosis with the same mutation, suggesting that there are more heterozygote animals in the population than previously thought.…”

Section: Discussionmentioning

confidence: 88%

Canine GM2‐Gangliosidosis Sandhoff Disease Associated with a 3‐Base Pair Deletion in the HEXB Gene

Wang

Henthorn

Galban

et al. 2017

Veterinary Internal Medicne

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Background GM2‐gangliosidosis is a fatal neurodegenerative lysosomal storage disease (LSD) caused by deficiency of either β‐hexosaminidase A (Hex‐A) and β‐hexosaminidase B (Hex‐B) together, or the GM2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency.ObjectivesTo characterize the phenotype and genotype of GM2‐gangliosidosis disease in an affected dog.AnimalsOne affected Shiba Inu and a clinically healthy dog.MethodsClinical and neurologic evaluation, brain magnetic resonance imaging (MRI), assays of lysosomal enzyme activities, and sequencing of all coding regions of HEXA, HEXB, and GM2A genes.ResultsA 14‐month‐old, female Shiba Inu presented with clinical signs resembling GM2‐gangliosidosis in humans and GM1‐gangliosidosis in the Shiba Inu. Magnetic resonance imaging (MRI) of the dog's brain indicated neurodegenerative disease, and evaluation of cerebrospinal fluid (CSF) identified storage granules in leukocytes. Lysosomal enzyme assays of plasma and leukocytes showed deficiencies of Hex‐A and Hex‐B activities in both tissues. Genetic analysis identified a homozygous, 3‐base pair deletion in the HEXB gene (c.618‐620delCCT).Conclusions and Clinical ImportanceClinical, biochemical, and molecular features are characterized in a Shiba Inu with GM2‐gangliosidosis. The deletion of 3 adjacent base pairs in HEXB predicts the loss of a leucine residue at amino acid position 207 (p.Leu207del) supporting the hypothesis that GM2‐gangliosidosis seen in this dog is the Sandhoff type. Because GM1‐gangliosidosis also exists in this breed with almost identical clinical signs, genetic testing for both GM1‐ and GM2‐gangliosidosis should be considered to make a definitive diagnosis.

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

Cited by 16 publications

References 35 publications

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

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

Canine GM2‐Gangliosidosis Sandhoff Disease Associated with a 3‐Base Pair Deletion in the HEXB Gene

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