A canine Arylsulfatase G ( ARSG ) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis
- 2 August 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (33), 14775-14780
- https://doi.org/10.1073/pnas.0914206107
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.Keywords
This publication has 43 references indexed in Scilit:
- Identifying cellular pathways modulated by Drosophila palmitoyl-protein thioesterase 1 functionNeurobiology of Disease, 2010
- Novel interactions of CLN5 support molecular networking between Neuronal Ceroid Lipofuscinosis proteinsBMC Cell Biology, 2009
- Insulin-like Growth Factor-I Prevents the Accumulation of Autophagic Vesicles and Cell Death in Purkinje Neurons by Increasing the Rate of Autophagosome-to-lysosome Fusion and DegradationPublished by Elsevier BV ,2009
- Secondary lipid accumulation in lysosomal diseaseBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008
- Neuronal ceroid lipofuscinosesBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008
- Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseasesBMC Genomics, 2008
- Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosisJournal of Inherited Metabolic Disease, 2007
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- Haploview: analysis and visualization of LD and haplotype mapsBioinformatics, 2004
- Neuronal Ceroid-lipofuscinosis in Nubian GoatsVeterinary Pathology, 1988