In other species: taurine cattle , sheep

Categories: Lysosomal storage disease , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 256731 (trait) , 608102 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009745: neuronal ceroid lipofuscinosis 5

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: One of several variants of neuronal ceroid lipofuscinosis (NCL) or Batten disease: CLN5; NCL5

Species-specific description: The neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules and early neuronal death. Affected Border collies present at 18-24 months of age. There is a genetic test available.

History: This disorder in dogs was first reported by Taylor and Farrow (1988).

Mapping: Melvile et al. (2005) genotyped animals in their pedigrees with microsatellites in "Likely candidate regions for the disease gene in Border collies based on the conserved synteny between the dog and the human genomes and the positions of NCL genes in human". Linkage analysis rejected chromosomes CFA6 and CFA37, but strongly implicated the region of CFA22 that is orthologous with the region of chromosome HSA13q21.1–q32 that contains CLN5, mutations in which give rise to this disorder in humans.

Molecular basis: Sequencing of the strong comparative positional candidate gene CLN5 (see Mapping section above) revealed to Melville et al. (2005) that the causative mutation in Border Collies is "a nonsense mutation (Q206X) within exon 4" which "should result in a protein product of a size similar to that of some mutations identified in human CLN5 and therefore the Border collie may make a good model for human NCL". CLN5 encodes a soluble lysosomal glycoprotein, the function of which is unknown, but it interacts with the proteins of TPP1 and CLN3 (Vesa et al., 2002). Melville et al. (2005) report the causative variant as c.619C>T or p.Q206X. This curator (T.L.) thinks that the original protein designation (Melville et al. 2005) is incorrect and should actually read p.Q207X, based on the RefSeq entry NM_001011556.1 of the dog CLN 5 transcript. Small deletion in Golden Retrievers: CLN5:c.934_935delAG; p.E312Vfs*6 (Gilliam et al., 2015), who explain that this mutation is "predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids". Kolicheski et al. (2016) reported that affected Australian Cattle Dogs have the same causal mutation as reported by Melville et al. (2005) in Border Collies.

Clinical features: Dogs present at 18-24 months of age with progressive behavioral changes, hyperactivity, dementia, aggression, loss of coordination, ataxia, delayed postural responses, blindness, and slow pupillary light responses (Taylor et al., 1988, Melville et al., 2005). Blind affected dogs have normal retinal structure on fundic and light microscopic examination, but have severe ultrastructural lesions (Taylor et al., 1988). Changes observed by MRI include slightly dilated cerebral sulci and cerebellar fissures, and left ventricular enlargement (Koie et al., 2004).

Pathology: There is widespread accumulation of autofluorescent storage granules in the cerebrum, cerebellum, and spinal cord. In the cerebellum there is Purkinje cell depletion, and those remaining contain eosinophilic, autofluorescent granules. Storage also occurs in the ganglion cells of the retina, peribronchial phagocytes, Kupffer cells, macrophages in the spleen, renal tubular epithelium, thyroid epithelial cells, enteric ganglia and submucosal plexus cells (Taylor et al., 1988).

Prevalence: The frequency of the c.619C>T allele is estimated at 3.5% in the Border collie population of Australia (Melville et al., 2005). Mizukami et al. (2016) reported the frequency of the c.619C>T allele as 0.035 in 500 Border collies in Japan. Villani et al. (2019) reported the c.619C>T variant to be homozygous in an affected mixed-breed dog of unknown parentage. They also reported a 87kb haplotype including the variant that is shared by this affected dog and the breeds in which this variant has been previously reported. Villani et al. (2019) concluded "that the NCL in all of these dogs stems from the same founding mutation event that may have predated the establishment of the modern dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed."

Control: Relatives of affected dogs should be tested. Avoid breeding affected dogs. If a carrier dog is bred with a dog that is DNA tested to not have the disease causing mutation, then all offspring need to be DNA tested to reduce the risk of future carrier by carrier matings.

Genetic testing: A test is available.

Breeds: Australian Cattle Dog (Dog) (VBO_0200088), Border Collie (Dog) (VBO_0200193), Golden Retriever (Dog) (VBO_0200610).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: