Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency.
NDUFAF8
complex I deficiency
mitochondrial disease
molecular diagnosis
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 01 2020
02 01 2020
Historique:
received:
30
10
2019
accepted:
02
12
2019
pubmed:
24
12
2019
medline:
18
4
2020
entrez:
24
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31866046
pii: S0002-9297(19)30465-3
doi: 10.1016/j.ajhg.2019.12.001
pmc: PMC7042492
pii:
doi:
Substances chimiques
Mitochondrial Proteins
0
NADH Dehydrogenase
EC 1.6.99.3
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
92-101Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM131795
Pays : United States
Organisme : Medical Research Council
ID : G016354/1
Pays : United Kingdom
Organisme : Department of Health
ID : PDF-2018-11-ST2-021
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : T32 GM008692
Pays : United States
Organisme : Wellcome Trust
ID : 203105/Z/16/Z
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : T32 AG000213
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS083726
Pays : United States
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
J Med Genet. 2016 Sep;53(9):634-41
pubmed: 27091925
Cell Mol Life Sci. 2018 Aug;75(16):3051-3067
pubmed: 29464284
Eye Brain. 2010;2:99-116
pubmed: 23226947
Cell Metab. 2012 Oct 3;16(4):538-49
pubmed: 22982022
Methods Cell Biol. 2007;80:93-119
pubmed: 17445690
Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5250-6
pubmed: 18676632
J Virol. 1998 Nov;72(11):8463-71
pubmed: 9765382
EMBO Rep. 2015 Jul;16(7):824-35
pubmed: 26071602
Mol Genet Metab. 2019 Jan;126(1):53-63
pubmed: 30473481
Am J Hum Genet. 2008 Oct;83(4):468-78
pubmed: 18940309
Cell Metab. 2011 Sep 7;14(3):428-34
pubmed: 21907147
Nat Biotechnol. 2001 May;19(5):434-9
pubmed: 11329012
Cell Metab. 2018 May 01;27(5):1026-1039.e6
pubmed: 29606596
Am J Hum Genet. 2018 Oct 4;103(4):592-601
pubmed: 30245030
Hum Mol Genet. 2015 Oct 1;24(19):5404-15
pubmed: 26160915
Semin Cell Dev Biol. 2018 Apr;76:154-162
pubmed: 28797839
Nat Genet. 1998 Dec;20(4):337-43
pubmed: 9843204
Science. 2013 Mar 15;339(6125):1328-1331
pubmed: 23371551
Mol Cell. 2014 Jul 17;55(2):332-41
pubmed: 25002142
Ann Neurol. 1996 Mar;39(3):343-51
pubmed: 8602753
Front Neurol. 2019 Apr 18;10:347
pubmed: 31105631
Trends Biochem Sci. 2016 Mar;41(3):245-260
pubmed: 26782138
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Brain. 2014 Nov;137(Pt 11):2903-8
pubmed: 25125611
Mitochondrion. 2019 Jul;47:294-297
pubmed: 30743023
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Ann Neurol. 2016 Feb;79(2):190-203
pubmed: 26506407
Brain. 2015 Dec;138(Pt 12):3503-19
pubmed: 26510951
Mol Cell. 2016 Aug 18;63(4):621-632
pubmed: 27499296
Clin Med (Lond). 2019 Jul;19(4):269-272
pubmed: 31308101
J Inherit Metab Dis. 1997 Aug;20(4):539-48
pubmed: 9266390
Sci Rep. 2017 Nov 15;7(1):15676
pubmed: 29142257
Nat Cell Biol. 2016 Dec;18(12):1311-1323
pubmed: 27842057
N Engl J Med. 2013 Oct 17;369(16):1502-11
pubmed: 24088041
J Neuropathol Exp Neurol. 2015 Jul;74(7):688-703
pubmed: 26083569
Mol Biosyst. 2010 Dec;6(12):2459-70
pubmed: 20922212
Nat Commun. 2017 Jun 12;8:15824
pubmed: 28604674
Cell Metab. 2017 Jan 10;25(1):128-139
pubmed: 27720676
Brain. 2010 Oct;133(10):2952-63
pubmed: 20819849