TY - JOUR
T1 - Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I
AU - Alahmad, Ahmad
AU - Nasca, Alessia
AU - Heidler, Juliana
AU - Thompson, Kyle
AU - Oláhová, Monika
AU - Legati, Andrea
AU - Lamantea, Eleonora
AU - Meisterknecht, Jana
AU - Spagnolo, Manuela
AU - He, Langping
AU - Alameer, Seham
AU - Hakami, Fahad
AU - Almehdar, Abeer
AU - Ardissone, Anna
AU - Alston, Charlotte L.
AU - McFarland, Robert
AU - Wittig, Ilka
AU - Ghezzi, Daniele
AU - Taylor, Robert W.
N1 - Funding Information:
Work in our laboratories is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, Newcastle University Centre for Ageing and Vitality [supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council (G016354/1)], the UK NIHR Biomedical Research Centre in Age and Age Related Diseases award to the Newcastle upon Tyne Hospitals NHS Foundation, the MRC/ESPRC Newcastle Molecular Pathology Node, the UK National Health Service Highly Specialised Service for Rare Mitochondrial Disorders, the Lily Foundation, the Pierfranco and Luisa Mariani Foundation, the E-Rare project GENOMIT and the Italian Ministry of Health (grant GR-2016-02361241). AA holds a PhD studentship funded by the Kuwait Civil Services Commission. CLA is supported by the National Institute for Health Research (NIHR Post-Doctoral Fellowship, PDF-2018-11-ST2-021). IW is supported by the Deutsche Forschungsgemeinschaft: (SFB 815/Z1 and EXC2026: Cardio Pulmonary Institute (CPI)) and by the BMBF mitoNET?German Network for Mitochondrial Disorders 01GM1906D. We thank the ?Cell line and DNA Bank of Genetic Movement Disorders and Mitochondrial Diseases? of the Telethon Network of Genetic Biobanks (grant GTB12001J) and Eurobiobank Network which supplied biological specimens. The authors would like to thank both families who participated in this study. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.
Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/11/6
Y1 - 2020/11/6
N2 - 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.
AB - 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.
KW - complex I
KW - Leigh syndrome
KW - mitochondrial disease
KW - NDUFC2
KW - OXPHOS
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U2 - 10.15252/emmm.202012619
DO - 10.15252/emmm.202012619
M3 - Article
C2 - 32969598
AN - SCOPUS:85091370813
VL - 12
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 11
M1 - e12619
ER -