A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis

Awano, Tomoyuki; Katz, Martin L.; O’Brien, Dennis P.; Sohár, István; Lobel, Peter; Coates, Joan R.; Khan, Shahnawaz; Johnson, Gayle C.; Giger, Urs; Johnson, Gary S.

doi:10.1016/j.ymgme.2006.02.016

Cited by 106 publications

(113 citation statements)

References 28 publications

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“…TPP1-null Dachshunds contain a frameshift mutation in the TPP1 gene (canine homolog of CLN2) and are a relevant animal model of CLN2 disease [1]. Affected animals display progressive neurological decline requiring euthanasia at 10-11 months old [15,26].…”

Section: Introductionmentioning

confidence: 99%

Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis

Vuillemenot

Kennedy

Cooper

et al. 2015

Molecular Genetics and Metabolism

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Section: Introductionmentioning

confidence: 99%

Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis

Vuillemenot

Kennedy

Cooper

et al. 2015

Molecular Genetics and Metabolism

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Gilliam

Kolicheski

Johnson

et al. 2015

Molecular Genetics and Metabolism

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We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs.

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“…10 Subunit c of mitochondrial adenosine triphosphate synthase (SCMAS) is the main storage material in the diseases caused by the mutations in CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, and CLCN7, whereas the accumulation of saposins (A and D) is recognized in some subtypes of NCL (those affected by mutations in CLN1 and CLN10). 10 Clinical and pathological features of the disease have been reported in several animal species, such as dogs, 1,2,13,14,18,19,22,23,26,28 cats, 16,21 sheep, 5,12,24,25 cattle, 6,8,11 goats, 4 horses, 9,31 and nonhuman primates. 29 Even in the veterinary field, mutations of causative genes have been identified: CLN5, 5 CLN6, 24,25 and CL10 30 in sheep; CLN5 in cattle 8 ; and CLN2 (TPP1), 1 CLN5, 18 CLN8, 13 and CLN10 (CTSD) 2 in dogs.…”

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confidence: 99%

Clinical and Pathologic Features of Neuronal Ceroid-Lipofuscinosis in a Ferret (Mustela putorius furo)

et al. 2011

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Clinical and pathologic features of neuronal ceroid-lipofuscinosis in a 4-month-old ferret are reported. Clinical signs including neurological symptoms appeared at 3 months of age and progressed rapidly. By magnetic resonance imaging, severe cerebral atrophy was recognized. Histopathologically, there was severe neuronal loss and diffuse astrogliosis with macrophage accumulations; lesions were found predominantly in the cerebral cortex. Intracytoplasmic pigments were observed in surviving neurons and macrophages throughout the brain. The pigments were intensely positive for periodic acid-Schiff, Luxol fast blue, and Sudan black B and exhibited a green autofluorescence. Electron microscopic examination revealed the accumulation of electron-dense granular material within lysosomes of neurons and macrophages. Immunohistochemically, a large number of saposin-positive granules accumulated in the neuronal cells, astrocytes, and macrophages of the lesions, but significant immunoreactivity for subunit c of mitochondrial adenosine triphosphate synthase was not observed. Based on these findings, the animal was diagnosed as affected by neuronal ceroid-lipofuscinosis.

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A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis

Cited by 106 publications

References 28 publications

Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis

Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis

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

Clinical and Pathologic Features of Neuronal Ceroid-Lipofuscinosis in a Ferret (Mustela putorius furo)

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