title: The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families.
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.
authors.affiliation: Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne, UK.
authors.forename: Helen A L
authors.initials: HA
authors.lastname: Tuppen
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Hogan
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Lisa
authors.initials: L
authors.lastname: Worgan
authors.forename: Mazhor
authors.initials: M
authors.lastname: Al-Dosary
authors.forename: Gabriele
authors.initials: G
authors.lastname: Saretzki
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Morris
authors.forename: Michael
authors.initials: M
authors.lastname: Clarke
authors.forename: Simon
authors.initials: S
authors.lastname: Jones
authors.forename: Anita M
authors.initials: AM
authors.lastname: Devlin
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.forename: Zofia M A
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D024101:Mitochondrial Proteins; D009245:NADH Dehydrogenase; C496411:NDUFS2 protein, human
references.citation: Q Rev Biophys. 1992 Aug;25(3):253-324
references.pmid: 1470679
references.citation: Am J Hum Genet. 2001 Jun;68(6):1344-52
references.pmid: 11349233
references.citation: Neurology. 2004 May 25;62(10):1899-901
references.pmid: 15159508
references.citation: Stem Cells. 2008 Feb;26(2):455-64
references.pmid: 18055443
references.citation: Am J Hum Genet. 2008 Jun;82(6):1306-15
references.pmid: 18513682
references.citation: Biochim Biophys Acta. 2000 Aug 15;1459(2-3):258-65
references.pmid: 11004438
references.citation: Mol Genet Metab. 2007 Sep-Oct;92(1-2):104-8
references.pmid: 17604671
references.citation: Ann Neurol. 2007 Jan;61(1):73-83
references.pmid: 17262856
references.citation: Neurology. 1999 Apr 12;52(6):1255-64
references.pmid: 10214753
references.citation: Brain. 2009 Apr;132(Pt 4):833-42
references.pmid: 19336460
references.citation: Cell. 2008 Jul 11;134(1):112-23
references.pmid: 18614015
references.citation: Acta Paediatr. 1997 Mar;86(3):326-9
references.pmid: 9099328
references.citation: Methods Mol Biol. 2000;132:365-86
references.pmid: 10547847
references.citation: Biochem Biophys Res Commun. 1998 Jun 29;247(3):751-8
references.pmid: 9647766
references.citation: J Med Genet. 2003 Mar;40(3):188-91
references.pmid: 12624137
references.citation: Methods Cell Biol. 2007;80:93-119
references.pmid: 17445690
references.citation: Biochim Biophys Acta. 2007 Mar;1772(3):373-81
references.pmid: 17289351
references.citation: J Biol Chem. 2006 Oct 27;281(43):32724-7
references.pmid: 16950771
references.citation: J Mol Med (Berl). 2005 Oct;83(10):786-94
references.pmid: 16142472
references.citation: Ann Neurol. 1999 Jun;45(6):787-90
references.pmid: 10360771
references.citation: J Med Genet. 2003 Dec;40(12):896-9
references.pmid: 14684687
references.citation: Nat Genet. 1999 Mar;21(3):260-1
references.pmid: 10080174
references.citation: Hum Genet. 2003 May;112(5-6):563-6
references.pmid: 12616398
references.citation: Methods. 2002 Apr;26(4):327-34
references.pmid: 12054923
references.citation: Biochim Biophys Acta. 2004 Dec 6;1659(2-3):136-47
references.pmid: 15576045
references.citation: Biochim Biophys Acta. 2010 May;1802(5):443-53
references.pmid: 20153825
references.citation: J Med Genet. 2004 Jan;41(1):14-7
references.pmid: 14729820
references.citation: Ann Neurol. 2001 Feb;49(2):195-201
references.pmid: 11220739
references.citation: Am J Hum Genet. 2009 Jun;84(6):718-27
references.pmid: 19463981
references.citation: Am J Hum Genet. 2008 Oct;83(4):468-78
references.pmid: 18940309
references.citation: Arch Neurol. 2005 Apr;62(4):659-61
references.pmid: 15824269
references.citation: J Clin Invest. 2005 Oct;115(10):2784-92
references.pmid: 16200211
references.citation: J Am Coll Cardiol. 2003 May 21;41(10):1786-96
references.pmid: 12767666
references.citation: J Clin Invest. 2004 Sep;114(6):837-45
references.pmid: 15372108
references.citation: J Biol Chem. 2003 Oct 31;278(44):43081-8
references.pmid: 12941961
references.citation: J Biol Chem. 2006 Apr 14;281(15):10374-80
references.pmid: 16478720
references.citation: Am J Hum Genet. 1998 Dec;63(6):1598-608
references.pmid: 9837812
references.citation: J Med Genet. 2010 Aug;47(8):507-12
references.pmid: 19542079
references.citation: Ann Neurol. 2004 Jan;55(1):58-64
references.pmid: 14705112
references.citation: Ann Neurol. 2008 Mar;63(3):405-8
references.pmid: 18306244
references.citation: Hum Mol Genet. 2004 Mar 15;13(6):659-67
references.pmid: 14749350
references.citation: J Mol Biol. 1997 Jan 31;265(4):409-18
references.pmid: 9034360
references.citation: Biochim Biophys Acta. 2004 Dec 6;1659(2-3):121-8
references.pmid: 15576043
references.citation: Am J Med Genet A. 2007 Jan 1;143A(1):33-41
references.pmid: 17152068
references.citation: Mol Genet Metab. 2009 Apr;96(4):196-200
references.pmid: 19167255
references.citation: EMBO J. 2007 Jul 11;26(13):3227-37
references.pmid: 17557076
references.citation: Hum Mol Genet. 2004 Oct 15;13(20):2461-72
references.pmid: 15317750
references.citation: Am J Hum Genet. 2008 Jan;82(1):32-8
references.pmid: 18179882
references.citation: Am J Med Genet. 2001 Spring;106(1):37-45
references.pmid: 11579423
references.citation: J Biol Chem. 2007 Mar 9;282(10):7582-90
references.pmid: 17209039
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W321-6
references.pmid: 15215403
references.citation: Mol Cell Biol. 2007 Jun;27(12):4228-37
references.pmid: 17438127
references.citation: Methods. 2008 Dec;46(4):281-7
references.pmid: 18948205