title: Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction.
abstract: Here we define a category of human, maternally inherited disorders that are characterized by a homoplasmic mtDNA pathogenic mutation with variable penetrance and a stereotypical clinical expression, usually restricted to a single tissue. Examples of such disorders include Leber's hereditary optic neuropathy, mitochondrial non-syndromic sensorineural hearing loss, and a form of mitochondrial hypertrophic cardiomyopathy. The mtDNA mutation is necessary, but not sufficient to induce the pathology, and multiple lines of evidence suggest a two-locus genetic model involving a primary mitochondrial mutation and a nuclear modifier. The nuclear modifier does not induce any pathology per se, but it contributes to the pathogenic effect of the mitochondrial mutation. The nuclear modifier could be a common functional polymorphism in a tissue-specific protein, possibly with mitochondrial location.
authors.affiliation: Dipartimento di Scienze Neurologiche, Universita' di Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy. carelli@neuro.unibo.it
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic; D002467:Cell Nucleus / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000235:genetics; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D005819:Genetic Markers