POSTER ABSTRACTS
#41 NDUFS7 missense variant in crossbred dogs with Leigh syndrome Matthias Christen1 , Anne Gregor2, Rodrigo Gutierrez Quintana3, Jos Bongers3, Angie Rupp3, Jacques Pendersi4, G. Diane Shelton5, Vidhya Jagannathan1, Christiane Zweier2, Tosso Leeb1 matthias.christen@vetsuisse.unibe.ch 1Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland, 2Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland, 3School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK, 4Vet-Extra Neurology, UK, 5Comparative Neuromuscular Laboratory, Department of Pathology, University of California, San Diego, USA We investigated two Chihuahua x Jack Russel Terrier mixed breed littermates. The dogs presented at four months of age with progressive signs of ataxia and dystonia affecting all limbs. MRI showed bilateral symmetrical lesions affecting cerebellar nuclei, caudate nucleus, rostral and caudal colliculi. Lactate levels were increased in urine, blood, and CSF. Histopathology of muscle cryosec- tions showed abnormal accumulations of mitochondria using the mitochondrial specific reactions cytochrome C oxidase and succinic dehydrogenase. Leigh syndrome was considered the most likely differential diagnosis for the two cases. Comparison of sequence data of one affected dog to 312 control genomes revealed a private homozygous protein-changing variant in NDUFS7, a known candidate gene for Leigh syndrome in humans. NDUFS7 encodes NADH:ubiquinone oxidoreductase core subunit S7, a subunit of complex I involved in the respiratory chain in mitochondria. The identified missense variant, XM_038568001.1:c.535G>A, is predicted to result in an amino acid substitution in the NDUFS7 protein, XP_038423929.1:(p.Val179Met). Several in silico prediction tools classified the substitution as pathogenic and deleterious. Sanger sequencing confirmed the presence of the NDUFS7 variant in homozygous state in both affected dogs and in heterozygous state in both parents. None of the additionally genotyped 39 Chihuahuas and 50 Jack Russel Terriers carried the mutant allele. To obtain functional confirmation of pathogenicity, we will use the GAL4/UAS system to induce knockdown of the NDUFS7 fly ortholog ND-20 in Drosophila, which is known to result in partial lethality. We will then overexpress wildtype and mutant canine and fly NDUFS7/ND-20 in this strain and evaluate rescue of the lethality phenotype.
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