A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis.
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.
Abitbol
Marie
M
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.
Thibaud
Jean-Laurent
JL
Olby
Natasha J
NJ
Hitte
Christophe
C
Puech
Jean-Philippe
JP
Maurer
Marie
M
Pilot-Storck
Fanny
F
Hédan
Benoit
B
Dréano
Stéphane
S
Brahimi
Sandra
S
Delattre
Delphine
D
André
Catherine
C
Gray
Françoise
F
Delisle
Françoise
F
Caillaud
Catherine
C
Bernex
Florence
F
Panthier
Jean-Jacques
JJ
Aubin-Houzelstein
Geneviève
G
Blot
Stéphane
S
Tiret
Laurent
L
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
D018528:ATP-Binding Cassette Transporters; D001192:Arylsulfatases