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© 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects’ fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects’ fibroblasts with wild‐type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module.

Details

Title
Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I
Author
Alahmad, Ahmad 1 ; Nasca, Alessia 2   VIAFID ORCID Logo  ; Heidler, Juliana 3 ; Thompson, Kyle 4 ; Oláhová, Monika 5 ; Legati, Andrea 2 ; Lamantea, Eleonora 2 ; Meisterknecht, Jana 3 ; Spagnolo, Manuela 2 ; He, Langping 6 ; Alameer, Seham 7 ; Hakami, Fahad 8 ; Almehdar, Abeer 9 ; Ardissone, Anna 10 ; Alston, Charlotte L 11 ; McFarland, Robert 11 ; Wittig, Ilka 12 ; Ghezzi, Daniele 13   VIAFID ORCID Logo  ; Taylor, Robert W 11   VIAFID ORCID Logo 

 Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Kuwait Medical Genetics Centre, Al‐Sabah Medical Area, Kuwait 
 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy 
 SFB815 Core Unit, Functional Proteomics, Medical School, Goethe‐Universität, Frankfurt am Main, Germany 
 Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK 
 Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK; Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK 
 Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 
 Pediatric Department, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia; King Abdullah International Medical Research Center, Jeddah, Saudi Arabia; King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia 
 Section of Molecular Medicine, King Abdulaziz Medical City‐WR, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia 
 Department of Medical Imaging, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City‐WR, National Guard Health Affairs, Jeddah, Saudi Arabia 
10  Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy 
11  Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 
12  SFB815 Core Unit, Functional Proteomics, Medical School, Goethe‐Universität, Frankfurt am Main, Germany; German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany 
13  Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy 
Section
Articles
Publication year
2020
Publication date
Nov 2020
Publisher
EMBO Press
ISSN
17574676
e-ISSN
17574684
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2457856096
Copyright
© 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.