title: Fatal manifestation of a de novo ND5 mutation: Insights into the pathogenetic mechanisms of mtDNA ND5 gene defects.
abstract: We report the de novo occurrence of a heteroplasmic 12706T-->C (12705C) ND5 mutation associated with the clinical expression of fatal Leigh syndrome. Phylogenetic analysis of several cases having the 12706C mutation confirmed that this mutation occurred independently in distinctive mtDNA backgrounds. In each of these cases, the low level of heteroplasmy and the association of the mutation with a deleterious phenotype indicated that the 12706C had a primary role in the expression of LS/MELAS in its carriers. Secondary structure analysis of the ND5 protein further supported the deleterious role of the 12706C mutation, as it was found to affect a functionally significant transmembrane domain that is likely responsible for the proton-translocation function of complex I.
authors.affiliation: Department of Anthropology, University of Pennsylvania, 325 University Museum, 3260 South Street, Philadelphia, PA 19104-6398, USA. zhadanov@sas.upenn.edu
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Zhadanov
authors.forename: Elena Ya
authors.initials: EY
authors.lastname: Grechanina
authors.forename: Yulia B
authors.initials: YB
authors.lastname: Grechanina
authors.forename: Vladislava A
authors.initials: VA
authors.lastname: Gusar
authors.forename: Natalya P
authors.initials: NP
authors.lastname: Fedoseeva
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.forename: Alfred
authors.initials: A
authors.lastname: Münnich
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Schurr
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D017124:Conserved Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D028361:Mitochondrial Diseases / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C481838:MT-ND5 protein, human; D042967:Electron Transport Complex I