title: The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?
abstract: Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease.
authors.affiliation: School of Veterinary Medicine, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Kiterie M E
authors.initials: KM
authors.lastname: Faller
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.affiliation: School of Veterinary Medicine, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Sharpe
authors.affiliation: Department of Histopathology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Anderson
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Darwent
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Celia
authors.initials: C
authors.lastname: Kun-Rodrigues
authors.affiliation: Department of Pathology, Tufts University School of Medicine and Tufts-New England Medical Center, Boston, Massachusetts.
authors.forename: Joseph
authors.initials: J
authors.lastname: Alroy
authors.affiliation: VetExtra Neurology, Broadleys, Stirling, United Kingdom.
authors.forename: Jacques
authors.initials: J
authors.lastname: Penderis
authors.affiliation: MRC Laboratory for Molecular Cell Biology, UCL Institute of Child Health, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.affiliation: School of Veterinary Medicine, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gutierrez-Quintana
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Guerreiro
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology / Q000662:veterinary*; D016133:Polymerase Chain Reaction; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D026901:Membrane Transport Proteins; D000091346:Tripeptidyl-Peptidase 1; C000717267:TPP1 protein, human
keywords: MFSD8; lysosomal storage disorder; neurodegeneration