title: A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis.
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.
authors.affiliation: Unité Mixte de Recherche 955 de Génétique Fonctionnelle et Médicale, Institut National de la Recherche Agronomique, and Unité Propre de Recherche de Neurobiologie, Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, F-94700 Maisons-Alfort, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Abitbol
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Thibaud
authors.forename: Natasha J
authors.initials: NJ
authors.lastname: Olby
authors.forename: Christophe
authors.initials: C
authors.lastname: Hitte
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Puech
authors.forename: Marie
authors.initials: M
authors.lastname: Maurer
authors.forename: Fanny
authors.initials: F
authors.lastname: Pilot-Storck
authors.forename: Benoit
authors.initials: B
authors.lastname: Hédan
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dréano
authors.forename: Sandra
authors.initials: S
authors.lastname: Brahimi
authors.forename: Delphine
authors.initials: D
authors.lastname: Delattre
authors.forename: Catherine
authors.initials: C
authors.lastname: André
authors.forename: Françoise
authors.initials: F
authors.lastname: Gray
authors.forename: Françoise
authors.initials: F
authors.lastname: Delisle
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillaud
authors.forename: Florence
authors.initials: F
authors.lastname: Bernex
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Panthier
authors.forename: Geneviève
authors.initials: G
authors.lastname: Aubin-Houzelstein
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.forename: Laurent
authors.initials: L
authors.lastname: Tiret
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000367:Age Factors; D000818:Animals; D001192:Arylsulfatases / Q000172:deficiency / Q000235:genetics*; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D002525:Cerebellar Cortex / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D004283:Dog Diseases / Q000201:enzymology / Q000235:genetics*; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009472:Neuronal Ceroid-Lipofuscinoses / Q000662:veterinary*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018528:ATP-Binding Cassette Transporters; D001192:Arylsulfatases