A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis

作者：Abitbol Marie^*; Thibaud Jean Laurent; Olby Natasha J; Hitte Christophe; Puech Jean Philippe; Maurer Marie; Pilot Storck Fanny; Hedan Benoit; Dreano Stephane; Brahimi Sandra; Delattre Delphine; Andre Catherine; Gray Francoise; Delisle Francoise; Caillaud Catherine; Bernex Florence; Panthier Jean Jacques; Aubin Houzelstein Genevieve; Blot Stephane; Tiret Laurent

来源：Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(33): 14775-14780.

DOI：10.1073/pnas.0914206107

• animal model
• ataxia
• dog
• neurodegenerative
• lysosome

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.

• 出版日期2010-8-17