In other species: Rhesus monkey

Categories: Lysosomal storage disease , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 606693 (trait) , 617225 (trait) , 610513 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Cross-species summary: One of several variants of neuronal ceroid lipofuscinosis (NCL) or Batten disease: CLN12; NCL12. In humans also known as "also known as Kufor-Rakeb syndrome, PARK9, and spastic paraplegia78" (Schmutz et al., 2019).

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. In the Tibetan terrier, changes in behavior and vision begin at 4-6 years of age. A genetic test is available.

Mapping: By conducting a GWAS on 19 affected and 15 control Tibetan Terriers, each genotyped with the Affymetrix Canine Genome 2.0 Array, Farias et al. (2011) mapped this disorder to a 1.3 Mb region of chromosome CFA2., which contains 18 genes, including a likely candidate ATP13A2. Later that same year, Wöhlke et al. (2011) reported an independent GWAS on 12 affected and 7 control Tibetan Terriers, each genotyped with the "127K canine Affymetrix SNP chip", which enabled them to map this disorder to the same region of CFA2 as Farias et al. (2011).

Molecular basis: By sequencing the likely positional candidate gene mentioned in the Mapping section (above), Farias et al (2011) identified the causative mutation as a single base deletion in ATP13A2, namely "c.1,623delG, which predicted a frame shift and premature termination codon (p.P541fsX597)". Later that same year, Wöhlke et al. (2011) confirmed the same mutation, but called it c.1620delG, and stated that it "causes an alternative splicing of exon 16 but not a frameshift mutation with a premature termination codon as previously supposed [by Farias et al., 2011]". They went on to explain that "As a result of the in-frame loss of exon 16, the ATP13A2 protein is shortened by 69 amino acids. Therefore, all NCL-affected Tibetan terriers in the present study can synthesize this shortened ATP13A2 protein. In humans, all three isoforms do not lack exon 16. This new insight on the structure of the mutated protein may explain why Tibetan terriers express only mild neurodegenerative symptoms and the onset of the disease is late in life." The sequence information provided by Wöhlke et al. (2011) in their Figure corresponds to transcript XM_005617949.3:c.1623del. Schmutz et al. (2019): "Whole genome sequence analysis of one of [three affected Australian Cattle] . . . dogs revealed a homozygous c.1118C > T variant in ATP13A2 that predicts a nonconservative p.(Thr373Ile) amino acid substitution. All 3 affected dogs were homozygous for this variant, which was heterozygous in 42 of 394 unaffected Australian Cattle Dogs, the remainder of which were homozygous for the c.1118C allele. "

Clinical features: Behavioral signs usually appear around 4 to 6 years of age (Katz et al., 2005, Katz et al., 2007, Farias et al., 2011). Signs include behavioral changes, cognitive decline, cerebellar ataxia, dementia, seizures, nervousness, aggressiveness, loss of training, hypersensitivity to stimuli, loss of coordination, tremors, retinal degeneration, depressed rod function, some impairment of cone function, moderate visual impairment in low light, but good visual acuity in bright light.

Pathology: There is widespread accumulation of autofluorescent lysosomal storage material throughout the cerebral cortex, retina, and cerebellum. Stored material appears as stacks of membranes in whorls or parallel arrays, or coarsely granular and lipid-like substances. Components of this material include glial fibrillary acidic protein (GFAP), and histone H4 (Katz et al., 2007).

Prevalence: As NCL is rare in other breeds, it is more common by comparison in the Tibetan terrier, which is likely due to the relatively small breeding population and adult onset of signs (Katz et al., 2005). Schmutz et al. (2019) "genotyped the [c.1118C>T] variant in a cohort of 397 Australian Cattle Dogs, which included the 3 known cases, dog D, 26 unaffected Australian Cattle Dogs older than 6 years of age and 367 population controls. This revealed a perfect association of the genotypes with the phenotype (Table 2). All three affected dogs carried the variant in homozygous state. Dog D, the sire of the two affected dogs was heterozygous (obligate carrier). Among the other 393 Australian Cattle dogs, we observed 352 dogs that were homozygous wildtype and 41 dogs that were heterozygous and presumably carriers for the disease. These data indicate that among the Australian Cattle Dogs that were sampled, the carrier frequency is around 10%. Because of sampling bias in our population, the carrier frequency among all Australian Cattle Dogs may be different. We also genotyped 555 dogs from genetically diverse breeds. None of these dogs carried the ATP13A2:c.1118C > T variant".

Control: Relatives of affected dogs should be tested. Avoid breeding affected or carrier dogs.

Genetic testing: There is a test available.

Breeds: Australian Cattle Dog (Dog) (VBO_0200088), Tibetan Terrier (Dog) (VBO_0201353).
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: