Dataset Information

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.

SUBMITTER: Abitbol M

PROVIDER: S-EPMC2930459 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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

Abitbol Marie M 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

Proceedings of the National Academy of Sciences of the United States of America 20100802 33

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 ...[more]

PMID: 20679209

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Project description:CLN2 neuronal ceroid lipofuscinosis is a rare hereditary neurodegenerative disorder characterized by deleterious sequence variants in TPP1 that result in reduced or abolished function of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Children with this disorder experience progressive neurological decline and vision loss starting around 2-4 years of age. Ocular disease is characterized by progressive retinal degeneration and impaired retinal function culminating in total loss of vision. Similar retinal pathology occurs in a canine model of CLN2 disease with a null variant in TPP1. A study using the dog model was performed to evaluate the efficacy of ocular gene therapy to provide a continuous, long-term source of human TPP1 (hTPP1) to the retina, inhibit retinal degeneration and preserve retinal function. TPP1-/- dogs received an intravitreal injection of 1 x 1012 viral genomes of AAV2.CAG.hTPP1 in one eye and AAV2.CAG.GFP in the contralateral eye at 4 months of age. Ophthalmic exams, in vivo ocular imaging and electroretinography were repeated monthly to assess retinal structure and function. Retinal morphology, hTPP1 and GFP expression in the retina, optic nerve and lateral geniculate nucleus, and hTPP1 concentrations in the vitreous were evaluated after the dogs were euthanized at end stage neurological disease at approximately 10 months of age. Intravitreal administration of AAV2.CAG.hTPP1 resulted in stable, widespread expression of hTPP1 throughout the inner retina, prevented disease-related declines in retinal function and inhibited disease-related cell loss and storage body accumulation in the retina for at least 6 months. Uveitis occurred in eyes treated with the hTPP1 vector, but this did not prevent therapeutic efficacy. The severity of the uveitis was ameliorated with anti-inflammatory treatments. These results indicate that a single intravitreal injection of AAV2.CAG.hTPP1 is an effective treatment to inhibit ocular disease progression in canine CLN2 disease.

Project description:The present review is focused on juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) due to a mutation in CLN3. Functional vision impairment occurring around 5-6 years of age is the first symptom in more than 80% of patients. Approximately 2 years later (though sometimes simultaneously), obvious signs of cognitive impairment appear. Behavior problems can occur in advance, especially in boys. These include anxious and depressed mood, aggressive behavior, and hallucinations, and even psychotic symptoms. Following the teens, severe dementia is present, including loss of memory, attention, and general reasoning abilities, as well as loss of independent adaptive skills such as mobility, feeding, and communicating. Sleep abnormalities, such as settling problems, nocturnal awakenings, and nightmares, are reported in more than half of patients. The vast majority, if not all, patients develop seizures, starting at approximately 10 years of age. Generalized tonic-clonic seizure occurs as the only type of seizure in approximately half of patients, and in combination with partial seizures in a third of patients. There seems to be no difference in seizure severity according to sex or genotype, and there is great variation in seizure activity among patients. Soon after diagnosis, patients begin to have slight ataxic symptoms, and at adolescence extrapyramidal symptoms (rigidity, bradykinesia, slow steps with flexion in hips and knees) occur with increasing frequency. Chewing and swallowing difficulties emerge as well, and food intake is hampered in the late teens. Disabling periodically involuntary movements may occur as well. A progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus-node dysfunction, ultimately leading to severe bradycardia and/or other conduction abnormalities, starts in the mid-teens. Patients are usually bedridden at 20 years of age, and death usually occurs in the third decade of life.

Dataset Information

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

Publications

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

Similar Datasets

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