Pathogenic bi-allelic mutations in NDUFAF8 cause Leigh syndrome with an isolated complex I deficiency

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,
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.
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Author:Charlotte L. Alston, Mike T. Veling, Juliana Heidler, Lucie S. Taylor, Joseph T. Alaimo, Andrew Y. Sung, Langping He, Sila Hopton, Alexander Broomfield, Julija Pavaine, Jullianne Diaz, Eyby Leon, Philipp Wolf, Robert McFarland, Holger Prokisch, Saskia B. Wortmann, Penelope E. Bonnen, Ilka Wittig, David J. Pagliarini, Robert W. Taylor
URN:urn:nbn:de:hebis:30:3-543976
DOI:http://dx.doi.org/10.1016/j.ajhg.2019.12.001
ISSN:0002-9297
ISSN:1537-6605
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=31866046
Parent Title (German):American journal of human genetics : AJHG
Publisher:Elsevier
Place of publication:New York, NY
Document Type:Article
Language:English
Date of Publication (online):2019/12/19
Date of first Publication:2019/12/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/05/04
Tag:NDUFAF8; complex I deficiency; mitochondrial disease; molecular diagnosis
Volume:106
Issue:1
First Page:92
Last Page:101
HeBIS PPN:465920349
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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