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.

Arylsulfatase G inactivation causes loss of heparan sulfate 3- O -sulfatase activity and mucopolysaccharidosis in mice

“…Arylsulfatase G (ARSG), a recently characterized lysosomal sulfatase with unknown physiological substrates (9), has been reported previously to be associated with an adult form of ceroid lipofuscinosis in dogs (10). In this study, we generated an ARSG-deficient mouse model by targeted disruption of the Arsg gene.…”

Characterization of Neuronal Ceroid-Lipofuscinosis in 3 Cats

“…Among both people and dogs, differences in clinical presentation, nervous system pathology, and the ultrastructural appearance of the lysosomal storage material are almost always associated with differences in the underlying mutations. [1][2][3]7,14,19,26,28 More than 360 mutations in at least 14 different genes coding for a variety of proteins, including lysosomal enzymes and membrane proteins associated with lysosomes, endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment membranes, and synaptic vesicles, underlie the human forms of NCL. 17 To date, in the veterinary literature, characterization of spontaneous causative mutations of NCL candidate genes has largely been limited to dogs (ARSG, 1 …”

“…26 In dogs, the detection of causative NCL candidate genes has been restricted to purebreds, including American Staffordshire Terriers (ARSG), 1 American Bulldogs (CTSD), 2 Tibetan Terriers (ATP13A2), 7 Dachshunds (TPP1 and PPT1), 13,28 an Australian Shepherd (CLN6), 14 English Setters (CLN8), 15 and Border Collies (CLN5). 19 Similarly, purebred sheep such as Borderdales (CLN5), 8 South Hampshires (CLN6), 25 and White Swedish Landraces (CTSD) 29 comprise the majority of reports of ovine NCL.…”

Le chien dans la pathologie et la génétique comparée: exemples de maladies et de gènes partagés entre l'homme et le chien

“…Concernant les maladies à composantes génétiques « simples » ou supposées simples, de nombreux travaux font actuellement état de l'identification de gènes responsables d'affections partagées entre l'homme et le chien, comme, par exemple, des rétinopa-thies (Wilk et al 2008), la sclérose amyothrophique latérale (Awano et al 2009), des maladies cardiaques (Meurs et al 2010), les lipofuscinoses neuronales canines (Abitbol et al 2010 ;Katz et al 2011), les épilepsies (Lohi et al 2005 ;Sepalla et al 2011), des maladies dermatologiques telle que l'ichtyose (Grall et al 2012), ou encore des anomalies comme le phénotype sans poil des chiens nus (Drogemuller et al, 2008).…”