TY  - JOUR
A1  - Alston, Charlotte L.
A1  - Veling, Mike T.
A1  - Heidler, Juliana
A1  - Taylor, Lucie S.
A1  - Alaimo, Joseph T.
A1  - Sung, Andrew Y.
A1  - He, Langping
A1  - Hopton, Sila
A1  - Broomfield, Alexander
A1  - Pavaine, Julija
A1  - Diaz, Jullianne
A1  - Leon, Eyby
A1  - Wolf, Philipp
A1  - McFarland, Robert
A1  - Prokisch, Holger
A1  - Wortmann, Saskia B.
A1  - Bonnen, Penelope E.
A1  - Wittig, Ilka
A1  - Pagliarini, David J.
A1  - Taylor, Robert W.
T1  - Pathogenic bi-allelic mutations in NDUFAF8 cause Leigh syndrome with an isolated complex I deficiency
T2  - American journal of human genetics : AJHG
N2  - 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.
KW  - mitochondrial disease
KW  - complex I deficiency
KW  - NDUFAF8
KW  - molecular diagnosis
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54397
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-543976
SN  - 0002-9297
SN  - 1537-6605
VL  - 106
IS  - 1
SP  - 92
EP  - 101
PB  - Elsevier
CY  - New York, NY
ER  -