title: A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia.
abstract: Hereditary paroxysmal dyskinesias (PxD) are a heterogeneous group of movement disorders classified by frequency, duration, and triggers of the episodes. A young-adult onset canine PxD has segregated as an autosomal recessive trait in Soft-Coated Wheaten Terriers. The medical records and videos of episodes from 25 affected dogs were reviewed. The episodes of hyperkinesia and dystonia lasted from several minutes to several hours and could occur as often as >10/day. They were not associated with strenuous exercise or fasting but were sometimes triggered by excitement. The canine PxD phenotype most closely resembled paroxysmal non-kinesigenic dyskinesia (PNKD) of humans. Whole genome sequences were generated with DNA from 2 affected dogs and analyzed in comparison to 100 control canid whole genome sequences. The two whole genome sequences from dogs with PxD had a rare homozygous PIGN:c.398C > T transition, which predicted the substitution of an isoleucine for a highly conserved threonine in the encoded enzyme. All 25 PxD-affected dogs were PIGN:c.398T allele homozygotes, whereas there were no c.398T homozygotes among 1185 genotyped dogs without known histories of PxD. PIGN encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors a variety of proteins including CD59 to the cell surface. Flow cytometry of PIGN-knockout HEK239 cells expressing recombinant human PIGN with the c.398T variant showed reduced CD59 expression. Mutations in human PIGN have been associated with multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1). Movement disorders can be a part of MCAHS1, but this is the first PxD associated with altered GPI anchor function.
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Kolicheski
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Johnson
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: Tendai
authors.initials: T
authors.lastname: Mhlanga-Mutangadura
authors.affiliation: Division of Animal Sciences, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, MO, USA.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Taylor
authors.affiliation: Division of Animal Sciences, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, MO, USA.|Informatics Institute, University of Missouri, Columbia, MO, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schnabel
authors.affiliation: Department of Immunoregulation, Research Institute for Microbial Diseases, and Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: Department of Immunoregulation, Research Institute for Microbial Diseases, and Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA. obriend@missouri.edu.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002819:Chorea / Q000235:genetics* / Q000662:veterinary; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010770:Phosphotransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: D017261:Glycosylphosphatidylinositols; C561296:PIGN protein, human; D010770:Phosphotransferases
keywords: Ethanolamine phosphate transferase-1; Glycosylphosphatidylinositol; Multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1); Phosphatidylinositol glycans