A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis

Abstract

The childhood neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that are progressive and ultimately fatal. An Australian Shepherd that exhibited a progressive neurological disorder with signs similar to human NCL was evaluated. The cerebral cortex, cerebellum, and retina were found to contain massive accumulations of autofluorescent inclusions characteristic of the NCLs. Nucleotide sequence analysis of DNA from the affected dog identified a T to C variant (c.829T>C) in exon 7 of CLN6. Mutations in the human ortholog underlie a late-infantile form of NCL in humans. The T-to-C transition results in a tryptophan to arginine amino acid change in the predicted protein sequence. Tryptophans occur at homologous positions in the CLN6 proteins from all 13 other vertebrates evaluated. The c.829T>C transition is a strong candidate for the causative mutation in this NCL-affected dog. Dogs with this mutation could serve as a model for the analogous human disorder.

Characterization of Neuronal Ceroid-Lipofuscinosis in 3 Cats

“…y The primarily green autofluorescence of the lipopigment in the present 3 cats was consistent with previous reports of NCL in cats, a ferret, and a Vietnamese potbelly pig, 4,6,21,23 but the storage material in most dogs with NCL tends to exhibit bright yellow autofluorescence at similar excitation wavelengths. 7,13,14,28 Interspecies diversity of the lipopigment constituents and/or differences in the fluorescence microscopy equipment and/or protocol may explain this apparent disparity. The typical distribution of CNS lesions observed in NCL correlates well with the pathological presentations of the present 3 cases.…”

“…26 In dogs, the detection of causative NCL candidate genes has been restricted to purebreds, including American Staffordshire Terriers (ARSG), 1 American Bulldogs (CTSD), 2 Tibetan Terriers (ATP13A2), 7 Dachshunds (TPP1 and PPT1), 13,28 an Australian Shepherd (CLN6), 14 English Setters (CLN8), 15 and Border Collies (CLN5). 19 Similarly, purebred sheep such as Borderdales (CLN5), 8 South Hampshires (CLN6), 25 and White Swedish Landraces (CTSD) 29 comprise the majority of reports of ovine NCL.…”

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

“…Among the animal species, NCLs have most frequently been reported in dogs. Previous studies have identified 9 different mutations in the canine orthologs of 8 of the 13 genes associated with human NCL as shown in Table 1 [10][11][12][13][14][15][16][17][18][19][20][21][22]. Prior to the discovery of the causative mutations, NCL was common in three dog breeds: the Tibetan Terrier, the Border Collie, and the American Bulldog [23][24][25][26].…”

“…The identification of the mutations responsible for the NCL in each of these breeds [12,[17][18][19] has led to the development of DNA tests that revealed the identity of asymptomatic heterozygous mutation carriers and, thereby, has assisted dog breeders in their efforts to reduce the incidence of NCL in these breeds [24,25]. The NCLs in most of the other dog breeds appear to be rare [10,11,[13][14][15][16]. DNA-based screening to identify mutation carriers would not be cost-effective in these breeds except in breeding lines where dogs with the disease have already been identified.…”

Le chien dans la pathologie et la génétique comparée: exemples de maladies et de gènes partagés entre l'homme et le chien

“…Concernant les maladies à composantes génétiques « simples » ou supposées simples, de nombreux travaux font actuellement état de l'identification de gènes responsables d'affections partagées entre l'homme et le chien, comme, par exemple, des rétinopa-thies (Wilk et al 2008), la sclérose amyothrophique latérale (Awano et al 2009), des maladies cardiaques (Meurs et al 2010), les lipofuscinoses neuronales canines (Abitbol et al 2010 ;Katz et al 2011), les épilepsies (Lohi et al 2005 ;Sepalla et al 2011), des maladies dermatologiques telle que l'ichtyose (Grall et al 2012), ou encore des anomalies comme le phénotype sans poil des chiens nus (Drogemuller et al, 2008).…”