title: Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder.
abstract: 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.
authors.affiliation: Mitochondrial Research Group, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.forename: Sharon
authors.initials: S
authors.lastname: Keers
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.forename: Philip
authors.initials: P
authors.lastname: Griffiths
authors.forename: Kirsi
authors.initials: K
authors.lastname: Huoponen
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Savontaus
authors.forename: Eeva
authors.initials: E
authors.lastname: Nikoskelainen
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Franco
authors.initials: F
authors.lastname: Carrara
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Veronika
authors.initials: V
authors.lastname: Karcagi
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.forename: I F M
authors.initials: IF
authors.lastname: de Coo
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: 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
chemical_list: D004272:DNA, Mitochondrial; D005819:Genetic Markers