Categories: Lysosomal storage disease , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600143 (trait) , 607837 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010830: neuronal ceroid lipofuscinosis 8

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: CLN8; NCL8

History: This disorder was first reported by Koppang (1970), who established a colony of English Setters in which the disorder segregated.

Mapping: Lingaas et al. (1998) conducted a genome scan with a panel of 103 microsatellites in a pedigree of "133 animals in three families with a total of 117 offspring". Subsequent genotyping of additional animals with a targetted set of markers from the genome scan enabled Lingaas et al. (1998) to report that "Linkage analysis showed three genetic markers to be linked to the disease locus with the closest marker at a distance of about 3 CM. Two other loci were linked with these markers making a linkage group of five genetic markers. The linkage group spanned a distance of 54 CM." At this time, this linkage group had not been allocated to a particular canine chromosome. By 2005, it was known that this linkage group corresponds to a region of chromosome CFA37 (Katz et al., 2005).

Molecular basis: In one of the early uses of the initial canine genome assembly, Katz et al. (2005) conducted megablast searches of the canine genome with all eight then-known human genes for ceroid lipofuscinosos. One of these (CLN8) was shown to be located on CFA37, near to the mapped location of this disorder (see Mapping section above). Sequencing of the canine CLN8 gene in affected English Setters revealed the causative mutation to be "a T-to-C transition in the CLN8 gene that predicts a p.L164P missense mutation". Whole-genome sequencing of an affected "mixed breed dog with Australian Shepherd and Blue Heeler ancestry" enabled Guo et al. (2014) to identify a nonsense mutation in the CLN8 gene of this dog, namely c.585G>A; p.Trp195*. Genotyping of archival samples enabled these authors to confirm the causality of this mutation. Hirz et al. (2017) reported "a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases" "of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam". Lingaas et al. (2018) reported a likely causal variant in the Saluki breed, namely a "single bp insertion (c.349dupT) in exon 2, introducing an immediate stop codon (p.Glu117*)" Guo et al. (2019) reported that an affected German Shorthaired Pointer was homozygous for the same nonsense variant as described by Guo et al. (2014).

Clinical features: Koppang (1992) and Guo et al. (2014) describe the disease in English Setter and Australian Shepherd dogs: From birth to 12-14 months of age, the dog presents as healthy. At 14-18 months, visual impairment and behavioural changes indicative of neurological degeneration, such as decreased responsiveness to voice commands and compulsive circling, develop. These symptoms worsen, leading to blindness, ataxia and eventual loss of motor function in the limbs. Seizures develop at 17-24 months, becoming more frequent and severe until death or euthanasia of the animal which usually occurs before the age of 27 months. IT thanks DVM student Steven Serb, who provided the basis of this contribution in May 2023.

Pathology: Koppang (1992) and Guo et al. (2014) describe the disease in English Setter and Australian Shepherd dogs: Gross pathology as well as MRI examination of the brain identifies diffuse brain atrophy and ventriculomegaly, which progresses alongside clinical signs. Histopathology identifies the accumulation of autofluorescent lysosomal storage material in neural tissue, which is pathognomonic for NCL. IT thanks DVM student Steven Serb, who provided the basis of this contribution in May 2023.

Breeds: Alpine Dachsbracke (Dog) (VBO_0200023), Australian Shepherd (Dog) (VBO_0200095), English Setter (Dog) (VBO_0200495), German Shorthaired Pointer (Dog) (VBO_0200583), Saluki (Dog) (VBO_0201171).
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: