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.

Unsolved issues related to human mitochondrial diseases

“…The main candidate genetic modifiers have been the mtDNA haplogroup and nuclear genes encoding mtDNA replication factors [6,7]. Despite longstanding and intensive efforts in the case of LHON the modifying nuclear genes have however remained elusive [8][9][10]. The influence of the mtDNA haplogroup has been repeatedly proposed but has remained a likely hypothesis in the absence of reliable functional assay [11,12].…”

Prévenir la transmission des mutations de l’ADN mitochondrial par don de cytoplasme : où en est-on ?

“…Le phénotype « surdité » de souris mutées dans le gène Ahl (age-related hearing loss gene), ne s'exprime en effet qu'en cas de co-mutation touchant un gène mitochondrial codant l'ARNt-Arg [14]. Chez l'humain, la pénétrance 3 incomplète des mutations de l'ADNmt responsables de la neuropathie optique de Leber 4 , serait liée à l'existence d'un ou plusieurs gènes nucléaires modificateurs localisés sur le chromosome X [15]. En conclusion, le transfert nucléaire qui aboutitof the meiotic spindle, taken from the maternal oocyte, revived the debate on the safety of these procedures.…”

Mitochondrial Genetics

“…70 However, the majority of research has focused on the identification of a nuclear-encoded susceptibility allele. 67,[71][72][73][74] Non-syndromic and aminoglycoside-induced sensorineuronal hearing loss is associated with m.1555A>G, a homoplasmic point mutation in the 12sRNA gene. 75 The variant alters a highly conserved region of 12sRNA, mutating the molecule to more closely resemble its bacterial homologue.…”