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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-016-0502-4) contains supplementary material, which is available to authorized users.

Whole genome sequencing for the investigation of canine mammary tumor inheritance - an initial assessment of high-risk breast cancer genes reveal BRCA2 and STK11 variants potentially associated with risk in purebred dogs

“…Furthermore, outside of ESS, there have been no breed-specific analyses. Considering that different WGS efforts in dogs have recently proven to be advantageous in elucidating genetic susceptibility to disease [22][23][24][25][26][27], differences in body types [28], as well as adaptions against parasites [29], we have compiled and processed WGS data to begin the exploration of breed-specific CMT-risk alleles and, in this initial report, to specifically reveal the coding variants detected in orthologs of the high-risk human breast cancer susceptibility genes.…”

Approach to canine paroxysmal dyskinesias

“…(1) Genetic causes -A genetic mutation of the brevican gene (BCAN) is implicated in episodic falling syndrome in Cavalier King Charles Spaniels (Gill et al 2012). A mutation has also been identified in the PIGN gene which is linked to a PD in Softcoated Wheaten terriers (Kolicheski et al 2017).…”

“…Age of onset is typically between eight months and three years (Kolicheski et al 2017;O'Brien et. al 2015).…”

“…al 2015). Episodes are characterised by rapid flexion and extension of pelvic limbs with truncal dystonia and progressive involvement of thoracic limbs in severe cases (Kolicheski et al 2017). An autosomal recessive trait of inheritance was proposed and a mutation in the gene PIGN was demonstrated.…”

“…Thus far, there is no proven benefit to treatment with benzodiazepines, antiepileptic drugs and muscle relaxants. Clinical signs may be progressive over time (Kolicheski et al 2017;O'Brien et. al 2015;Shelton 2004) but medical therapy with acetazolamide has been shown to be effective with some dogs achieving complete resolution of the dyskinesia (O'Brien et.…”