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