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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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