Alston 2020 Am J Hum Genet

[[Has title::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 (2020) Pathogenic bi-allelic mutations in NDUFAF8 cause Leigh syndrome with an isolated complex I deficiency. Am J Hum Genet 106:92-101.]]

» [[Has info::PMID: 31866046 Open Access]]

Was written by::Alston CL, Was written by::Veling MT, Was written by::Heidler J, Was written by::Taylor LS, Was written by::Alaimo JT, Was written by::Sung AY, Was written by::He L, Was written by::Hopton S, Was written by::Broomfield A, Was written by::Pavaine J, Was written by::Diaz J, Was written by::Leon E, Was written by::Wolf P, Was written by::McFarland R, Was written by::Prokisch H, Was written by::Wortmann SB, Was written by::Bonnen PE, Was written by::Wittig I, Was written by::Pagliarini DJ, Was written by::Taylor RW (Was published in year::2020) Was published in journal::Am J Hum Genet

Abstract: [[has abstract::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.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.]] • Keywords: has publicationkeywords::NDUFAF8, has publicationkeywords::Complex I deficiency, has publicationkeywords::Mitochondrial disease, has publicationkeywords::Molecular diagnosis • Bioblast editor: [[has editor::Plangger M]] • O2k-Network Lab: Was published by MiPNetLab::DE Frankfurt Wittig I

Labels: MiParea: MiP area::Respiration, MiP area::nDNA;cell genetics 

Organism: Organism::Human  Tissue;cell: tissue and cell::Fibroblast  Preparation: Preparation::Permeabilized cells, Preparation::Intact cells  Enzyme: Enzyme::Complex I 

Coupling state: Coupling states::LEAK, Coupling states::ROUTINE, Coupling states::OXPHOS, Coupling states::ET  Pathway: Pathways::N, Pathways::NS  HRR: Instrument and method::Oxygraph-2k 

additional label::Labels, additional label::2020-01