2. Academic Validation
  3. Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I

Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I

  • EMBO Mol Med. 2020 Nov 6;12(11):e12619. doi: 10.15252/emmm.202012619.
Ahmad Alahmad 1 2 3,  Alessia Nasca 4,  Juliana Heidler 5,  Kyle Thompson 1 2,  Monika Oláhová 1 6,  Andrea Legati 4,  Eleonora Lamantea 4,  Jana Meisterknecht 5,  Manuela Spagnolo 4,  Langping He 1 7,  Seham Alameer 8 9 10,  Fahad Hakami 11,  Abeer Almehdar 12,  Anna Ardissone 13,  Charlotte L Alston 1 2 7,  Robert McFarland 1 2 7,  Ilka Wittig # 5 14,  Daniele Ghezzi # 4 15,  Robert W Taylor # 1 2 7
Affiliations

Affiliations

  • 1 Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
  • 2 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • 3 Kuwait Medical Genetics Centre, Al-Sabah Medical Area, Kuwait.
  • 4 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 5 SFB815 Core Unit, Functional Proteomics, Medical School, Goethe-Universität, Frankfurt am Main, Germany.
  • 6 Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 7 NHS Highly Specialised Service for Rare Mitochondrial Disorders, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 8 Pediatric Department, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia.
  • 9 King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.
  • 10 King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
  • 11 Section of Molecular Medicine, King Abdulaziz Medical City-WR, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
  • 12 Department of Medical Imaging, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City-WR, National Guard Health Affairs, Jeddah, Saudi Arabia.
  • 13 Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 14 German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
  • 15 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
  • # Contributed equally.
PMID: 32969598 DOI: 10.15252/emmm.202012619
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.

Keywords

Leigh syndrome; NDUFC2; OXPHOS; complex I; mitochondrial disease.

Figures