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The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families

Tuppen, HA; Hogan, VE; He, L; Blakely, EL; Worgan, L; Al-Dosary, M; Saretzki, G; Alston, CL; Morris, AA; Clarke, M; et al. Tuppen, HA; Hogan, VE; He, L; Blakely, EL; Worgan, L; Al-Dosary, M; Saretzki, G; Alston, CL; Morris, AA; Clarke, M; Jones, S; Devlin, AM; Mansour, S; Chrzanowska-Lightowlers, ZM; Thorburn, DR; McFarland, R; Taylor, RW (2010) The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families. BRAIN, 133. 2952 - 2963. ISSN 0006-8950 https://doi.org/10.1093/brain/awq232
SGUL Authors: Mansour, Sahar

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Abstract

Isolated complex I deficiency is the most frequently observed oxidative phosphorylation defect in children with mitochondrial disease, leading to a diverse range of clinical presentations, including Leigh syndrome. For most patients the genetic cause of the biochemical defect remains unknown due to incomplete understanding of the complex I assembly process. Nonetheless, a plethora of pathogenic mutations have been described to date in the seven mitochondrial-encoded subunits of complex I as well as in 12 of the nuclear-encoded subunits and in six assembly factors. Whilst several mitochondrial DNA mutations are recurrent, the majority of these mutations are reported in single families. We have sequenced core structural and functional nuclear-encoded subunits of complex I in a cohort of 34 paediatric patients with isolated complex I deficiency, identifying pathogenic mutations in 6 patients. These included a novel homozygous NDUFS1 mutation in an Asian child with Leigh syndrome, a previously identified NDUFS8 mutation (c.236C>T, p.P79L) in a second Asian child with Leigh-like syndrome and six novel, compound heterozygous NDUFS2 mutations in four white Caucasian patients with Leigh or Leigh-like syndrome. Three of these children harboured an identical NDUFS2 mutation (c.875T>C, p.M292T), which was also identified in conjunction with a novel NDUFS2 splice site mutation (c.866+4A>G) in a fourth Caucasian child who presented to a different diagnostic centre, with microsatellite and single nucleotide polymorphism analyses indicating that this was due to an ancient common founder event. Our results confirm that NDUFS2 is a mutational hotspot in Caucasian children with isolated complex I deficiency and recommend the routine diagnostic investigation of this gene in patients with Leigh or Leigh-like phenotypes.

Item Type: Article
Additional Information: © The Author(s) 2010. Published by Oxford University Press on behalf of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Electrophoresis, Polyacrylamide Gel, Female, Haplotypes, Humans, Infant, Leigh Disease, Male, Mitochondria, Mitochondrial Proteins, Mutation, NADH Dehydrogenase, Polymerase Chain Reaction, Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Neurosciences & Neurology, CLINICAL NEUROLOGY, NEUROSCIENCES, mitochondrial disease, Leigh syndrome, complex I deficiency, NDUFS2, recurrent mutation, MITOCHONDRIAL COMPLEX, ND3 GENE, SUBUNITS, DISEASE, ENCEPHALOMYOPATHY, IDENTIFICATION, PATIENT, NADH, ELECTROPHORESIS, 11 Medical And Health Sciences, CARDIOMYOPATHY, 17 Psychology And Cognitive Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: BRAIN
ISSN: 0006-8950
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Dates:
DateEvent
1 October 2010Published
Web of Science ID: WOS:000282423100011
URI: https://openaccess.sgul.ac.uk/id/eprint/107135
Publisher's version: https://doi.org/10.1093/brain/awq232

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