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A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107 (33), pp.14775-80. ⟨10.1073/pnas.0914206107⟩, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (33), pp.14775-80. ⟨10.1073/pnas.0914206107⟩, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (33), pp.14775-14780. ⟨10.1073/pnas.0914206107⟩, Proceedings of the National Academy of Sciences; Vol 107, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (33), pp.14775-80. 〈10.1073/pnas.0914206107〉, Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107 (33), pp.14775-14780. ⟨10.1073/pnas.0914206107⟩
- Publication Year :
- 2010
- Publisher :
- HAL CCSD, 2010.
-
Abstract
- Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs’ disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G ( ARSG ) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.
- Subjects :
- Male
Candidate gene
[SDV]Life Sciences [q-bio]
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
[SDV.GEN] Life Sciences [q-bio]/Genetics
0403 veterinary science
Gene Frequency
Catalytic Domain
Missense mutation
Dog Diseases
ComputingMilieux_MISCELLANEOUS
Arylsulfatases
Genetics
0303 health sciences
Multidisciplinary
Reverse Transcriptase Polymerase Chain Reaction
Sulfatase
Age Factors
Chromosome Mapping
04 agricultural and veterinary sciences
Biological Sciences
3. Good health
Pedigree
Cerebellar cortex
dog
lysosome
Female
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Genotype
040301 veterinary sciences
Molecular Sequence Data
Mutation, Missense
Locus (genetics)
Biology
Polymorphism, Single Nucleotide
Cell Line
03 medical and health sciences
Cerebellar Cortex
Dogs
Microscopy, Electron, Transmission
Neuronal Ceroid-Lipofuscinoses
medicine
Animals
Humans
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
030304 developmental biology
[SDV.GEN]Life Sciences [q-bio]/Genetics
Genetic heterogeneity
Gene Expression Profiling
animal model
Haplotype
ataxia
medicine.disease
Molecular biology
Chromosomes, Mammalian
Haplotypes
[ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
neurodegenerative
Neuronal ceroid lipofuscinosis
ATP-Binding Cassette Transporters
[ SDV.GEN ] Life Sciences [q-bio]/Genetics
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Subjects
Details
- Language :
- English
- ISSN :
- 00278424 and 10916490
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107 (33), pp.14775-80. ⟨10.1073/pnas.0914206107⟩, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (33), pp.14775-80. ⟨10.1073/pnas.0914206107⟩, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (33), pp.14775-14780. ⟨10.1073/pnas.0914206107⟩, Proceedings of the National Academy of Sciences; Vol 107, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (33), pp.14775-80. 〈10.1073/pnas.0914206107〉, Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107 (33), pp.14775-14780. ⟨10.1073/pnas.0914206107⟩
- Accession number :
- edsair.doi.dedup.....d7f99a349b1ffd444be4441ce501dbb0