A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy
Several enzymes are involved in fatty acid oxidation, which is a key process in mitochondrial energy production. Inherited defects affecting any step of fatty acid oxidation can result in clinical disease. We present here an extended family of German Hunting Terriers with 10 dogs affected by clinica...
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ftdoajarticles:oai:doaj.org/article:49923d882cad4f93915e03840e17cddc 2023-05-15T15:50:53+02:00 A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy Vincent Lepori Franziska Mühlhause Adrian C. Sewell Vidhya Jagannathan Nils Janzen Marco Rosati Filipe Miguel Maximiano Alves de Sousa Aurélie Tschopp Gertraud Schüpbach Kaspar Matiasek Andrea Tipold Tosso Leeb Marion Kornberg 2018-05-01T00:00:00Z https://doi.org/10.1534/g3.118.200084 https://doaj.org/article/49923d882cad4f93915e03840e17cddc EN eng Oxford University Press http://g3journal.org/lookup/doi/10.1534/g3.118.200084 https://doaj.org/toc/2160-1836 2160-1836 doi:10.1534/g3.118.200084 https://doaj.org/article/49923d882cad4f93915e03840e17cddc G3: Genes, Genomes, Genetics, Vol 8, Iss 5, Pp 1545-1554 (2018) dog canis lupus familiaris metabolism myopathy beta-oxidation very long-chain acyl-CoA dehydrogenase deficiency whole genome sequencing animal model Genetics QH426-470 article 2018 ftdoajarticles https://doi.org/10.1534/g3.118.200084 2022-12-31T11:30:27Z Several enzymes are involved in fatty acid oxidation, which is a key process in mitochondrial energy production. Inherited defects affecting any step of fatty acid oxidation can result in clinical disease. We present here an extended family of German Hunting Terriers with 10 dogs affected by clinical signs of exercise induced weakness, muscle pain, and suspected rhabdomyolysis. The combination of clinical signs, muscle histopathology and acylcarnitine analysis with an elevated tetradecenoylcarnitine (C14:1) peak suggested a possible diagnosis of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD). Whole genome sequence analysis of one affected dog and 191 controls revealed a nonsense variant in the ACADVL gene encoding acyl-CoA dehydrogenase very long chain, c.1728C>A or p.(Tyr576*). The variant showed perfect association with the phenotype in the 10 affected and more than 500 control dogs of various breeds. Pathogenic variants in the ACADVL gene have been reported in humans with similar myopathic phenotypes. We therefore considered the detected variant to be the most likely candidate causative variant for the observed exercise induced myopathy. To our knowledge, this is the first description of this disease in dogs, which we propose to name exercise induced metabolic myopathy (EIMM), and the identification of the first canine pathogenic ACADVL variant. Our findings provide a large animal model for a known human disease and will enable genetic testing to avoid the unintentional breeding of affected offspring. Article in Journal/Newspaper Canis lupus Directory of Open Access Journals: DOAJ Articles G3 Genes|Genomes|Genetics 8 5 1545 1554 |
institution |
Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
dog canis lupus familiaris metabolism myopathy beta-oxidation very long-chain acyl-CoA dehydrogenase deficiency whole genome sequencing animal model Genetics QH426-470 |
spellingShingle |
dog canis lupus familiaris metabolism myopathy beta-oxidation very long-chain acyl-CoA dehydrogenase deficiency whole genome sequencing animal model Genetics QH426-470 Vincent Lepori Franziska Mühlhause Adrian C. Sewell Vidhya Jagannathan Nils Janzen Marco Rosati Filipe Miguel Maximiano Alves de Sousa Aurélie Tschopp Gertraud Schüpbach Kaspar Matiasek Andrea Tipold Tosso Leeb Marion Kornberg A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy |
topic_facet |
dog canis lupus familiaris metabolism myopathy beta-oxidation very long-chain acyl-CoA dehydrogenase deficiency whole genome sequencing animal model Genetics QH426-470 |
description |
Several enzymes are involved in fatty acid oxidation, which is a key process in mitochondrial energy production. Inherited defects affecting any step of fatty acid oxidation can result in clinical disease. We present here an extended family of German Hunting Terriers with 10 dogs affected by clinical signs of exercise induced weakness, muscle pain, and suspected rhabdomyolysis. The combination of clinical signs, muscle histopathology and acylcarnitine analysis with an elevated tetradecenoylcarnitine (C14:1) peak suggested a possible diagnosis of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD). Whole genome sequence analysis of one affected dog and 191 controls revealed a nonsense variant in the ACADVL gene encoding acyl-CoA dehydrogenase very long chain, c.1728C>A or p.(Tyr576*). The variant showed perfect association with the phenotype in the 10 affected and more than 500 control dogs of various breeds. Pathogenic variants in the ACADVL gene have been reported in humans with similar myopathic phenotypes. We therefore considered the detected variant to be the most likely candidate causative variant for the observed exercise induced myopathy. To our knowledge, this is the first description of this disease in dogs, which we propose to name exercise induced metabolic myopathy (EIMM), and the identification of the first canine pathogenic ACADVL variant. Our findings provide a large animal model for a known human disease and will enable genetic testing to avoid the unintentional breeding of affected offspring. |
format |
Article in Journal/Newspaper |
author |
Vincent Lepori Franziska Mühlhause Adrian C. Sewell Vidhya Jagannathan Nils Janzen Marco Rosati Filipe Miguel Maximiano Alves de Sousa Aurélie Tschopp Gertraud Schüpbach Kaspar Matiasek Andrea Tipold Tosso Leeb Marion Kornberg |
author_facet |
Vincent Lepori Franziska Mühlhause Adrian C. Sewell Vidhya Jagannathan Nils Janzen Marco Rosati Filipe Miguel Maximiano Alves de Sousa Aurélie Tschopp Gertraud Schüpbach Kaspar Matiasek Andrea Tipold Tosso Leeb Marion Kornberg |
author_sort |
Vincent Lepori |
title |
A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy |
title_short |
A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy |
title_full |
A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy |
title_fullStr |
A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy |
title_full_unstemmed |
A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy |
title_sort |
nonsense variant in the acadvl gene in german hunting terriers with exercise induced metabolic myopathy |
publisher |
Oxford University Press |
publishDate |
2018 |
url |
https://doi.org/10.1534/g3.118.200084 https://doaj.org/article/49923d882cad4f93915e03840e17cddc |
genre |
Canis lupus |
genre_facet |
Canis lupus |
op_source |
G3: Genes, Genomes, Genetics, Vol 8, Iss 5, Pp 1545-1554 (2018) |
op_relation |
http://g3journal.org/lookup/doi/10.1534/g3.118.200084 https://doaj.org/toc/2160-1836 2160-1836 doi:10.1534/g3.118.200084 https://doaj.org/article/49923d882cad4f93915e03840e17cddc |
op_doi |
https://doi.org/10.1534/g3.118.200084 |
container_title |
G3 Genes|Genomes|Genetics |
container_volume |
8 |
container_issue |
5 |
container_start_page |
1545 |
op_container_end_page |
1554 |
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1766385906433916928 |