Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder.
Mitochondrial DNA (mtDNA) mutations are a major cause of human disease. A large number of different molecular defects ultimately compromise oxidative phosphorylation, but it is not clear why the same biochemical defect can cause diverse clinical phenotypes. There is emerging evidence that nuclear genes modulate the phenotype of primary mtDNA disorders. Here, we define an X-chromosomal haplotype that interacts with specific MTND mutations to cause visual failure in the most common mtDNA disease, Leber hereditary optic neuropathy. This effect is independent of the mtDNA genetic background and explains the variable penetrance and sex bias that characterizes this disorder.
Hudson
Gavin
G
Mitochondrial Research Group, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.
Keers
Sharon
S
Yu-Wai-Man
Patrick
P
Griffiths
Philip
P
Huoponen
Kirsi
K
Savontaus
Marja-Liisa
ML
Nikoskelainen
Eeva
E
Zeviani
Massimo
M
Carrara
Franco
F
Horvath
Rita
R
Karcagi
Veronika
V
Spruijt
Liesbeth
L
de Coo
I F M
IF
Smeets
Hubert J M
HJ
Chinnery
Patrick F
PF
D000483:Alleles; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D028361:Mitochondrial Diseases / Q000453:epidemiology* / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000453:epidemiology / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D012737:Sex Factors; D018709:Statistics, Nonparametric
D004272:DNA, Mitochondrial; D005819:Genetic Markers