Fatal manifestation of a de novo ND5 mutation: Insights into the pathogenetic mechanisms of mtDNA ND5 gene defects.
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.
Zhadanov
Sergey I
SI
Department of Anthropology, University of Pennsylvania, 325 University Museum, 3260 South Street, Philadelphia, PA 19104-6398, USA. zhadanov@sas.upenn.edu
Grechanina
Elena Ya
EY
Grechanina
Yulia B
YB
Gusar
Vladislava A
VA
Fedoseeva
Natalya P
NP
Lebon
Sophie
S
Münnich
Alfred
A
Schurr
Theodore G
TG
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
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C481838:MT-ND5 protein, human; D042967:Electron Transport Complex I