NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

Christen, M., Gregor, A., Gutierrez Quintana, R. , Bongers, J., Rupp, A., Penderis, J., Shelton, G. D., Jagannathan, V., Zweier, C. and Leeb, T. (2024) NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model. Scientific Reports, 14, 2975. (doi: 10.1038/s41598-024-53314-7) (PMID:38316835) (PMCID:PMC10844639)

Abstract

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rupp, Dr Angie and Bongers, Dr Jos and Gutierrez Quintana, Mr Rodrigo
• Authors: Christen, M., Gregor, A., Gutierrez Quintana, R., Bongers, J., Rupp, A., Penderis, J., Shelton, G. D., Jagannathan, V., Zweier, C., and Leeb, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2024 The Author(s)
• First Published: First published in Scientific Reports 14:2975
• Publisher Policy: Reproduced under a Creative Commons license