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Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency

Lookup NU author(s): Dr Charlotte Alston, Lucie Taylor, Dr Langping He, Sila Hopton, Professor Bobby McFarland, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019 The Author(s). Leigh syndrome is one of the most common neurological phenotypes observed in pediatric mitochondrial disease presentations. It is characterized by symmetrical lesions found on neuroimaging in the basal ganglia, thalamus, and brainstem and by a loss of motor skills and delayed developmental milestones. Genetic diagnosis of Leigh syndrome is complicated on account of the vast genetic heterogeneity with >75 candidate disease-associated genes having been reported to date. Candidate genes are still emerging, being identified when “omics” tools (genomics, proteomics, and transcriptomics) are applied to manipulated cell lines and cohorts of clinically characterized individuals who lack a genetic diagnosis. NDUFAF8 is one such protein; it has been found to interact with the well-characterized complex I (CI) assembly factor NDUFAF5 in a large-scale protein-protein interaction screen. Diagnostic next-generation sequencing has identified three unrelated pediatric subjects, each with a clinical diagnosis of Leigh syndrome, who harbor bi-allelic pathogenic variants in NDUFAF8. These variants include a recurrent splicing variant that was initially overlooked due to its deep-intronic location. Subject fibroblasts were found to express a complex I deficiency, and lentiviral transduction with wild-type NDUFAF8-cDNA ameliorated both the assembly defect and the biochemical deficiency. Complexome profiling of subject fibroblasts demonstrated a complex I assembly defect, and the stalled assembly intermediates corroborate the role of NDUFAF8 in early complex I assembly. This report serves to expand the genetic heterogeneity associated with Leigh syndrome and to validate the clinical utility of orphan protein characterization. We also highlight the importance of evaluating intronic sequence when a single, definitively pathogenic variant is identified during diagnostic testing.


Publication metadata

Author(s): Alston CL, Veling MT, Heidler J, Taylor LS, Alaimo JT, Sung AY, He L, Hopton S, Broomfield A, Pavaine J, Diaz J, Leon E, Wolf P, McFarland R, Prokisch H, Wortmann SB, Bonnen PE, Wittig I, Pagliarini DJ, Taylor RW

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2020

Volume: 106

Issue: 1

Pages: 92-101

Print publication date: 02/01/2020

Online publication date: 19/12/2019

Acceptance date: 19/12/2019

Date deposited: 06/01/2020

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: https://doi.org/10.1016/j.ajhg.2019.12.001

DOI: 10.1016/j.ajhg.2019.12.001


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