Neuronal ceroid lipofuscinosis in Merino sheep

Cook, R W; Jolly, R. D.; Palmer, David N.; Tammen, Imke; Broom, Murray F.; McKinnon, Rick

doi:10.1111/j.1751-0813.2002.tb10847.x

Cited by 44 publications

(44 citation statements)

References 22 publications

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“…Naturally occurring NCLs in South Hampshire and Merino sheep (OCL6) and nclf mice have been localized to CLN6 (22)(23)(24). The severe and progressive neurodegeneration of the cerebral cortex is accompanied by astrocytosis and elevated expression of the radical scavenger protein Mn-SOD (24,25).…”

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confidence: 99%

Defective Endoplasmic Reticulum-resident Membrane Protein CLN6 Affects Lysosomal Degradation of Endocytosed Arylsulfatase A

Heine

Koch

Storch

et al. 2004

Journal of Biological Chemistry

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Variant late infantile neuronal ceroid lipofuscinosis, a lysosomal storage disorder characterized by progressive mental deterioration and blindness, is caused by mutations in a polytopic membrane protein (CLN6) with unknown intracellular localization and function. In this study, transient transfection of BHK21 cells with CLN6 cDNA and immunoblot analysis using peptide-specific CLN6 antibodies demonstrated the expression of a ϳ27-kDa protein that does not undergo proteolytic processing. Cross-linking experiments revealed the presence of CLN6 dimers. Using double immunofluorescence microscopy, epitope-tagged CLN6 was shown to be retained in the endoplasmic reticulum (ER) with no colocalization with the cis-Golgi or lysosomal markers. The translocation into the ER and proper folding were confirmed by the N-linked glycosylation of a mutant CLN6 polypeptide. Pulse-chase labeling of fibroblasts from CLN6 patients and from sheep (OCL6) and mouse (nclf) models of the disease followed by immunoprecipitation of cathepsin D indicated that neither the synthesis, sorting nor the proteolytic processing of this lysosomal enzyme was affected in CLN6-defective cells. However, the degradation of the endocytosed index protein arylsulfatase A was strongly reduced in all of the mutant CLN6 cell lines compared with controls. These data suggest that defects in the ER-resident CLN6 protein lead to lysosomal dysfunctions, which may result in lysosomal accumulation of storage material.

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Defective Endoplasmic Reticulum-resident Membrane Protein CLN6 Affects Lysosomal Degradation of Endocytosed Arylsulfatase A

Heine

Koch

Storch

et al. 2004

Journal of Biological Chemistry

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“…7 In some affected animals, especially Miniature Schnauzers and White Swedish Landrace sheep, sphingolipid activator proteins (SAPs) are the primary component of storage bodies. 3 In humans, NCLs are a common cause of neurodegeneration in children, with some forms additionally or primarily presenting in adults. Human NCLs traditionally have been classified by age of onset combined with ultrastructural phenotype: granular osmiophilic deposits characteristic of SAPs versus the lamellar appearance of SCMAS.…”

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Neuronal Ceroid-Lipofuscinosis in a Holstein Steer

Hafner

Flynn²,

Harmon

et al. 2005

J VET Diagn Invest

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A young, partially blind Holstein steer was affected by mild cerebral atrophy. Formalin-fixed cerebral gray matter was diffusely yellow brown. Microscopically, there were eosinophilic, autofluorescent granules primarily in the cytoplasm of cerebral neurons. There was also extensive retinal atrophy with complete loss of the rod and cone layers. Ultrastructural examination of affected cerebral neurons revealed a mixture of granular osmiophilic and lamellar patterns in the cytoplasmic storage bodies. This suggests the existence of neuronal ceroid-lipofuscinosis in the Holstein breed.

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“…13,20 Seizures occur in all forms of human NCL except a subset of CLN4. 6,7 Seizures are far less common in animals, reported in only 3 species: Merino sheep, 3 English setter dogs, 10 and 1 domestic cat. 20 Though these 3 features may have developed later in the course of the disease (had the pig survived long enough), an alternative, perhaps more likely scenario given the severity of the CNS lesions, is that these features were not characteristics of the disease in this pig.…”

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confidence: 99%

“…6,7 NCL has been reported in numerous animal species. 3,5,12,18 Reported clinical signs include blindness, seizures, progressive psychomotor deterioration, altered behavior, and premature death. 3,8,10,18 The genetic mutation has been identified in only 1 species-Swedish Landrace sheep-in which there is a mutation in the gene encoding the lysosomal enzyme cathepsin D. 17 In 4 other species, a specific genetic mutation is strongly suspected: a CLN8 mutation in English Setter dogs 9 and mnd mice, 15 and a CLN6 mutation in South Hampshire sheep 3 and Merino sheep.…”

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confidence: 99%

Neuronal Ceroid Lipofuscinosis in a Vietnamese Pot-bellied Pig (Sus scrofa)

Cesta¹,

Mozzachio²,

Little³

et al. 2006

Vet Pathol

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Abstract. The neuronal ceroid ipofuscinoses (NCL) are a group of heritable, neurodegenerative, storage diseases, typically with an autosomal recessive mode of inheritance. Cytoplasmic accumulation of storage material in cells of the nervous system and, variably in other tissues, characterizes NCL. NCL has been reported in many animal species, but to the authors' knowledge, this is the first report of the disease in a pig. Blindness and seizures are common clinical signs of disease, neither of which was a feature in this pig. The lesions were restricted to the central nervous system, which was diffusely affected, with the most severe lesions in the hippocampus, cerebral cortex, and cerebellum. The histologic lesions included neuronal loss and gliosis, which contributed to mild cerebrocortical and cerebellar atrophy and accumulation of autofluorescent storage material in neurons and glial cells. The storage material had morphologic, histologic, and ultrastructural properties typical of NCL.

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Neuronal ceroid lipofuscinosis in Merino sheep

Abstract: NCL in Merino sheep is a subunit c-storing disease, clinically and pathologically similar to NCL in South Hampshire sheep. We propose that the disease in both breeds represents mutation at the same gene locus in chromosomal region OAR7q13-15.

Cited by 44 publications

References 22 publications

Defective Endoplasmic Reticulum-resident Membrane Protein CLN6 Affects Lysosomal Degradation of Endocytosed Arylsulfatase A

Defective Endoplasmic Reticulum-resident Membrane Protein CLN6 Affects Lysosomal Degradation of Endocytosed Arylsulfatase A

Neuronal Ceroid-Lipofuscinosis in a Holstein Steer

Neuronal Ceroid Lipofuscinosis in a Vietnamese Pot-bellied Pig (Sus scrofa)

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