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Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED)
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 thei...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397061/ https://www.ncbi.nlm.nih.gov/pubmed/32660061 http://dx.doi.org/10.3390/genes11070774 |
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author | Nessler, Jasmin Hug, Petra Mandigers, Paul J. J. Leegwater, Peter A. J. Jagannathan, Vidhya Das, Anibh M. Rosati, Marco Matiasek, Kaspar Sewell, Adrian C. Kornberg, Marion Hoffmann, Marina Wolf, Petra Fischer, Andrea Tipold, Andrea Leeb, Tosso |
author_facet | Nessler, Jasmin Hug, Petra Mandigers, Paul J. J. Leegwater, Peter A. J. Jagannathan, Vidhya Das, Anibh M. Rosati, Marco Matiasek, Kaspar Sewell, Adrian C. Kornberg, Marion Hoffmann, Marina Wolf, Petra Fischer, Andrea Tipold, Andrea Leeb, Tosso |
author_sort | Nessler, Jasmin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7397061 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73970612020-08-05 Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED) Nessler, Jasmin Hug, Petra Mandigers, Paul J. J. Leegwater, Peter A. J. Jagannathan, Vidhya Das, Anibh M. Rosati, Marco Matiasek, Kaspar Sewell, Adrian C. Kornberg, Marion Hoffmann, Marina Wolf, Petra Fischer, Andrea Tipold, Andrea Leeb, Tosso Genes (Basel) Article 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. MDPI 2020-07-09 /pmc/articles/PMC7397061/ /pubmed/32660061 http://dx.doi.org/10.3390/genes11070774 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Nessler, Jasmin Hug, Petra Mandigers, Paul J. J. Leegwater, Peter A. J. Jagannathan, Vidhya Das, Anibh M. Rosati, Marco Matiasek, Kaspar Sewell, Adrian C. Kornberg, Marion Hoffmann, Marina Wolf, Petra Fischer, Andrea Tipold, Andrea Leeb, Tosso Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED) |
title | Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED) |
title_full | Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED) |
title_fullStr | Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED) |
title_full_unstemmed | Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED) |
title_short | Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED) |
title_sort | mitochondrial pck2 missense variant in shetland sheepdogs with paroxysmal exercise-induced dyskinesia (ped) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397061/ https://www.ncbi.nlm.nih.gov/pubmed/32660061 http://dx.doi.org/10.3390/genes11070774 |
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