A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy

G3: Genes, Genomes, Genetics

article

Vincent Lepori¹  Franziska Mühlhause²  Adrian C. Sewell⁴  Vidhya Jagannathan¹  Nils Janzen⁵  Marco Rosati⁷  Filipe Miguel Maximiano Alves de Sousa⁸  Aurélie Tschopp⁸  Gertraud Schüpbach⁸  Kaspar Matiasek⁷  Andrea Tipold³  Tosso Leeb¹  Marion Kornberg² 

[1] Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Switzerland;Veterinary Clinic for Small Animals Elmer-Kornberg-Schanen, 54294 Trier, Germany;Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559, Germany;Biocontrol, Laboratory for Veterinary Diagnostics, 55218 Ingelheim, Germany;Screening-Labor Hannover, 30430, Germany;Department of Clinical Chemistry, Hannover Medical School, 30625, Germany;Section of Clinical & Comparative Neuropathology, Institute of Veterinary Pathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany;Veterinary Clinic for Small Animals Elmer-Kornberg-Schanen, 54294 Trier, Germany

关键词: dog;    canis lupus familiaris;    metabolism;    myopathy;    beta-oxidation;    very long-chain acyl-CoA dehydrogenase deficiency;    whole genome sequencing;    animal model;   

DOI  :  10.1534/g3.118.200084

学科分类：社会科学、人文和艺术（综合）

来源: Genetics Society of America

【 摘 要 】

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.

【 授权许可】

CC BY|CC BY-NC