Neuronal Ceroid Lipofuscinosis 8, NCL8

 

Gene: CLN8

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

English Setter mutation: Substitution, CLN8 gene; c.4911 T>C, p.(L164P), exon2

Australian Shepherd, German Shorthaired Pointer mutation: Substitution, CLN8 gene; c.585 G>A, p.(W195 STOP)

Alpine Dachsbracke mutation: Deletion, CLN8 gene; c.-14679_18669, deletion of NCL8 gene

Saluki mutation: Insertion, CLN8 gene; c.349 ins T, p.(E117 STOP)

Medical system: Neurologic, lysosomal storage disease

Breeds: Alpine Dachsbracke, Australian Kelpie, Australian Shepherd, Beagle, English Setter, German Shorthaired Pointer, Golden Retriever, Gordon Setter, Irish Red and White Setter, Irish Setter, Saluki

Age of onset of symptoms: Around the age of 14 to 18 months

Neuronal Ceroid Lipofuscinosis describes a family of genetic diseases that affect the function of lysosomes within the cell.  NCL8 is a form of this disease seen in a number of breeds due to independent mutations within the CLN8 gene.   Affected individuals are deficient for an enzyme necessary for normal cell metabolism, resulting in an accumulation of metabolic waste products, particularly within nerve cells.  Affected animals develop clinical neurological signs at around 14 to 18 months of age, which may include lethargy, ataxia, blindness and myoclonic epilepsy.  There can also be behavioral changes such as aggression, lack of interest in playing with other dogs, lack of response to commands, fear and hallucinations.  Affected animals either die from convulsions or are euthanized, usually before the age of 2 years.

 

References:
OMIA link: [1506-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Cerda-Gonzalez S, Packer RA, Garosi L, et al. (2021) International veterinary canine dyskinesia task force ECVN consensus statement: Terminology and classification. J Vet Intern Med 35:1218-1230 [pubmed/33769611]

Story BD, Miller ME, Bradbury AM, et al. (2020) Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7:80. [pubmed/32219101]

Guo J, Johnson GS, Cook J, et al. (2019) Neuronal ceroid lipofuscinosis in a German Shorthaired Pointer associated with a previously reported CLN8 nonsense variant. Mol Genet Metab Rep 21:100521.  [pubmed/31687336]

Lingaas F, Guttersrud OA, Arnet E, Espenes A. (2018) Neuronal ceroid lipofuscinosis in Salukis is caused by a single base pair insertion in CLN8. Anim Genet 49:52-58.  [pubmed/29446145]

Hirz M, Drögemüller M, Schänzer A, et al. (2017) Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog. Mol Genet Metab 120:269-277.  [pubmed/28024876]

Guo J, Johnson GS, Brown HA, et al. (2014) A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry. Mol Genet Metab 112:302-9. [pubmed/24953404]

Katz ML, Khan S, Awano T et al. (2005) A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Comm 327:541-547. [pubmed/15629147]

Koppang N. (1992) English setter model and juvenile ceroid-lipofuscinosis in man. Am J Med Genet. 42(4):599-604. [pubmed/1609842]

 

Contributed by: Sam Boutin-Bigras, Negi Nikita Negi, class of 2027, Veterinary Medicine Faculty, University of Montreal.  (Translation: DWS).