Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog

Hirz, Manuela; Drögemüller, Michaela; Schänzer, Anne; Jagannathan, Vidhya; Dietschi, Elisabeth; Hh, Goebel; Hecht, Werner; Laubner, Steffi; Schmidt, Martin J.; Steffen, Frank; Hilbe, Monika; Köhler, Kernt; Drögemüller, Cord; Herden, Christiane

doi:10.1016/j.ymgme.2016.12.007

Cited by 24 publications

(14 citation statements)

References 49 publications

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“…This approach enables one to screen a dog for candidate mutations in all of the known NCL genes at once with the added advantage of enabling one to search for candidate disease causing mutations in other genes if an affected dog does not have a mutation in one of the known NCL genes. To date, the mutations responsible for NCL have been discovered in Australian Cattle Dogs, Golden Retrievers, Chinese Crested dogs, Chihuahuas, Cane Corsos, and Alpenlandische Dachsbrackes using the whole genome sequencing approach (Faller et al, 2016; Gilliam et al, 2015; Guo et al, 2015; Hirz et al, 2016; Kolicheski et al, 2017a; Kolicheski et al, 2016). In total to date, 12 mutations in eight genes have been identified as causative for NCL in dogs (Table 1).…”

Section: Canine Ncls With Known Causative Mutationsmentioning

confidence: 99%

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: Canine Ncls With Known Causative Mutationsmentioning

confidence: 99%

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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“…) and NCL in two Alpenländische Dachsbracke dogs was suggested to be caused by deletion of the entire CLN8 gene (Hirz et al . ). The present report adds a further novel defective allele variant to the list of possible mutations associated with NCL, due to a 1‐bp insertion that introduces a stop codon in the second half of exon 2.…”

Section: Discussionmentioning

confidence: 97%

“…; Hirz et al . ) , CLN10 (also known as CTSD; Awano et al . ) and CLN12 (also known as ATP13A2; Farias et al .…”

Section: Introductionmentioning

confidence: 99%

Neuronal ceroid lipofuscinosis in Salukis is caused by a single base pair insertion in CLN8

Lingaas

Arnet

et al. 2018

Animal Genetics

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Neuronal ceroid lipofuscinoses (NCLs) are heterogenic inherited lysosomal storage diseases that have been described in a number of species including humans, sheep, cattle, cats and a number of different dog breeds, including Salukis. Here we present a novel genetic variant associated with the disease in this particular breed of dog. In a clinical case, a Saluki developed progressive neurological signs, including disorientation, anxiety, difficulties in eating, seizures and loss of vision, and for welfare reasons, was euthanized at 22 months of age. Microscopy showed aggregation of autofluorescent storage material in the neurons of several brain regions and also in the retina. The aggregates showed positive staining with Sudan black B and periodic acid Schiff, all features consistent with NCL. Whole genome sequencing of the case and both its parents, followed by variant calling in candidate genes, identified a new variant in the CLN8 gene: a single bp insertion (c.349dupT) in exon 2, introducing an immediate stop codon (p.Glu117*). The case was homozygous for the insertion, and both parents were heterozygous. A retrospective study of a Saluki from Australia diagnosed with NCL identified this case as being homozygous for the same mutation. This is the fourth variant identified in CLN8 that causes NCL in dogs.

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“…The clinical signs and fluorescent microscopic results were consistent with a diagnosis of NCL. Because whole‐genome sequencing previously had proven to be an effective strategy for identifying genetic variants responsible for NCL in dogs, a whole‐genome sequence was generated with DNA from Dog A. The resulting sequence data had 31‐fold average coverage of the CanFam3.1 reference assembly and are available in the National Center for Biotechnology Information Sequence Read Archives (accession SRS1692083).…”

Section: Methodsmentioning

confidence: 99%

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

Kolicheski

Johnson

Villani

et al. 2017

Veterinary Internal Medicne

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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.

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Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog

Cited by 24 publications

References 49 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

Neuronal ceroid lipofuscinosis in Salukis is caused by a single base pair insertion in CLN8

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

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