title: A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers.
abstract: A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations; however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, USA.
authors.forename: Fabiana H G
authors.initials: FH
authors.lastname: Farias
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.forename: Gary S
authors.initials: GS
authors.lastname: Johnson
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wininger
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Taylor
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schnabel
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: McKay
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Sanders
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
authors.forename: Eija H
authors.initials: EH
authors.lastname: Seppälä
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wade
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Dennis P
authors.initials: DP
authors.lastname: O'Brien
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D055106:Genome-Wide Association Study; D006801:Humans; D008279:Magnetic Resonance Imaging; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D006180:Proton-Translocating ATPases / Q000235:genetics*
chemical_list: D006180:Proton-Translocating ATPases