Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background.
Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G-->A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G-->A or 14484T-->C mutations are present in specific subgroups of haplogroup J (J2 for 11778G-->A and J1 for 14484T-->C) and when the 3460G-->A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G-->A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder.
Mitochondrial Research Group, Department of Ophthalmology and Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Gavin
G
Hudson
Valerio
V
Carelli
Liesbeth
L
Spruijt
Mike
M
Gerards
Catherine
C
Mowbray
Alessandro
A
Achilli
Angela
A
Pyle
Joanna
J
Elson
Neil
N
Howell
Chiara
C
La Morgia
Maria Lucia
ML
Valentino
Kirsi
K
Huoponen
Marja-Liisa
ML
Savontaus
Eeva
E
Nikoskelainen
Alfredo A
AA
Sadun
Solange R
SR
Salomao
Rubens
R
Belfort
Philip
P
Griffiths
Patrick
P
Yu-Wai-Man
Rene F M
RF
de Coo
Rita
R
Horvath
Massimo
M
Zeviani
Hubert J T
HJ
Smeets
Antonio
A
Torroni
Patrick F
PF
Chinnery
D000328:Adult; D001766:Blindness / Q000235:genetics; D004272:DNA, Mitochondrial; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D019683:Penetrance; D012307:Risk Factors; D012737:Sex Factors
D004272:DNA, Mitochondrial