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.
Hudson
Gavin
G
Mitochondrial Research Group, Department of Ophthalmology and Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Carelli
Valerio
V
Spruijt
Liesbeth
L
Gerards
Mike
M
Mowbray
Catherine
C
Achilli
Alessandro
A
Pyle
Angela
A
Elson
Joanna
J
Howell
Neil
N
La Morgia
Chiara
C
Valentino
Maria Lucia
ML
Huoponen
Kirsi
K
Savontaus
Marja-Liisa
ML
Nikoskelainen
Eeva
E
Sadun
Alfredo A
AA
Salomao
Solange R
SR
Belfort
Rubens
R
Griffiths
Philip
P
Yu-Wai-Man
Patrick
P
de Coo
Rene F M
RF
Horvath
Rita
R
Zeviani
Massimo
M
Smeets
Hubert J T
HJ
Torroni
Antonio
A
Chinnery
Patrick F
PF
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