Neuronal Ceroid Lipofuscinosis 5, NCL5

 

Gene: CLN5

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:

Border Collie mutation: Substitution, CLN5 gene; c.619 C>T, p.(Q207 STOP), exon4

Golden retriever mutation: Deletion, CLN5 gene; c.935_936 del, p.(E312V fs STOP 6)

Medical systems: Neurological, lysosomal storage disease

Breeds: Australian Cattle Dog, Border Collie, German Shepherd, Golden Retriever, Great Pyrenees, Koolie, Labrador Retriever

Age of onset of symptoms: Around the age of 15 to 20 months

Neuronal Ceroid Lipofuscinosis (NCL) is a family of genetic diseases that affect the function of lysosomes within the cell.   One particular form of the disease, NCL5, affects Border Collies due to a mutation of the CLN5 gene and Golden Retrievers due to a different mutation of the same gene.  Affected individuals have a dysfunction of an enzyme necessary for normal cell metabolism resulting in an accumulation of metabolic waste products within the cells.  Nerve cells are particularly affected and animals develop clinical neurological signs such as ataxia, convulsions, lethargy and blindness around the age of 15 to 20 months. They may also display behavioral changes such as lack of interest in playing with other dogs, lack of response to commands, hallucinations, fear and aggression. Affected animals usually die before the age of 32 months.

 

References:

OMIA link: [1482-9615]

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]

Stee K, Van Poucke M, Lowrie M, et al. (2023) Phenotypic and genetic aspects of hereditary ataxia in dogs. J Vet Intern Med. [pubmed/37341581]

Meiman, EJ, Kick, GR, Jensen CA, et al. (2022) Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis. Dev Neurobiol 82:326-344.  [pubmed/35427439]

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]

Villani NA, Bullock G, Michaels JR, et al. (2019) A mixed breed dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs. Mol Genet Metab [pubmed/31101435]

Katz ML, Rustad E, Robinson GO. (2017) Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions. Neurobiol Dis. 108:277-287. [pubmed/28860089]

Kolicheski A, Johnson GS, O’Brien DP, et al. (2016) Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies. J Vet Intern Med. 30(4):1149-58. [pubmed/27203721]

Gilliam D, Kolicheski A, Johnson GS, et al. (2015) Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5. Molecular Genetics and Metabolism 115:101-9. [pubmed/25934231]

Mizukami K, Kawamichi T, Koie H, et al. (2012) Neuronal ceroid lipofuscinosis in Border Collie dogs in Japan: clinical and molecular epidemiological study (2000-2011). Scientific WorldJournal. 2012:383174. [pubmed/22919312]

Melville SA, Wilson CL, Chiang CS, et al. (2005) A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics 86:287-294. [pubmed/16033706]