A One Base Pair Deletion in the Canine ATP13A2 Gene Causes Exon Skipping and Late-Onset Neuronal Ceroid Lipofuscinosis in the Tibetan Terrier

Abstract

Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5–7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71–84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies.

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

“…We obtained blood anti-coagulated with EDTA from 18 members of the Golden Retriever family including the common grandmother, the [18,19] † There are as yet no known canine models for CLN3, CLN4, CLN11, CLN13 or CLN14; CLN9 is not in current use. ‡ A canine lysosomal storage disease originally described as a NCL [20] is more appropriately classified as a mucopolysaccharidosis [21,22].…”

“…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].…”

“…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].…”

Pantothenate Kinase-Associated Neurodegeneration

“…ATP13A2 mutations have been shown to cause a late onset neurodegenerative phenotype in dogs [79]. ATP13A2 encodes a lysosomal divalent cation transporter [80].…”

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

“…A similar link between NCL and Kufor-Rakeb disease was established when ATP13A2 mutations were recently identified in Tibetean terriers with NCL [147,148]. In this context it is interesting that some patients with NCL have parkinsonism and that brains of NCL patients caused by Cathepsin D deficiency (CLN10) show intense alphasynuclein staining [144].…”