A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by progressive neurodegeneration and accumulation of autofluorescent storage granules. A 9 month old Miniature Dachshund presented with NCL-like signs that included disorientation, ataxia, weakness, visual impairment and behavioral changes. Neurons throughout the CNS contained autofluorescent lysosomal inclusions with granular osmiophilic deposit (GROD) ultrastructure characteristic of classical infantile NCL (INCL). Human INCL is an autosomal recessive disorder that results from mutations in PPT1, a gene that encodes the enzyme palmitoyl protein thioesterase 1 (PPT1; EC 3.1.22). Resequencing of PPT1 from the affected dog revealed that the dog was homozygous for a single nucleotide insertion in exon 8 (PPT1 c.736_737insC), upstream from the His289 active site. Brain tissue from this dog lacked PPT1 activity. The sire and dam of the propositus were heterozygous for the c.736_737insC mutation; whereas, 127 unrelated Dachshunds were homozygous for the wildtype allele. This is the first reported instance of canine NCL caused by a mutation in PPT1.

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.…”

“…Mutations in at least 14 different genes underlie different forms of human NCL, 17 and mutations in at least 8 different genes underlie different forms of canine NCL. [1][2][3]7,14,15,26,28 The differences in the causative mutations account for much of the heterogeneity in disease phenotype. Even different mutations within the same gene can result in a notable divergence in disease progression among affected people.…”

“…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.…”