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Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED).
- Source :
-
Genes [Genes (Basel)] 2020 Jul 09; Vol. 11 (7). Date of Electronic Publication: 2020 Jul 09. - Publication Year :
- 2020
-
Abstract
- Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G>A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.
- Subjects :
- Animals
Blood Pressure
Chorea etiology
Chorea genetics
Chorea pathology
Dog Diseases etiology
Dog Diseases pathology
Dogs
Female
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
Chorea veterinary
Dog Diseases genetics
Motor Activity
Mutation, Missense
Phosphoenolpyruvate Carboxykinase (ATP) genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2073-4425
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Genes
- Publication Type :
- Academic Journal
- Accession number :
- 32660061
- Full Text :
- https://doi.org/10.3390/genes11070774