A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia
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- 作者：Ana L. Kolicheski ; Gary S. Johnson ; Tendai Mhlanga-Mutangadura…
- 关键词：Glycosylphosphatidylinositol ; Multiple congenital anomalies ; hypotonia ; seizures syndrome ; 1 (MCAHS1) ; Phosphatidylinositol glycans ; Ethanolamine phosphate transferase ; 1
- 刊名：neurogenetics
- 出版年：2017
- 出版时间：January 2017
- 年：2017
- 卷：18
- 期：1
- 页码：39-47
- 全文大小：709KB
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Neurosciences; Human Genetics; Molecular Medicine;
- 出版者：Springer Berlin Heidelberg
- ISSN：1364-6753
- 卷排序：18
文摘
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.