title: Characterization of the human mitochondrial aconitase gene (ACO2).
abstract: We have cloned and characterized the ACO2 gene on human chromosome 22q13, which encodes the essential iron-dependent metabolic enzyme mitochondrial aconitase. We determined that the ACO2 gene comprises 18 translated exons distributed over approximately 35 kilobasepairs (kbp) of DNA. We have shown that the ACO2 mRNA is 2.7kb in length and is expressed ubiquitously, and we can detect multiple isoforms of the ACO2 protein. As others had reported the existence of biochemically active electrophoretic variants of mitochondrial aconitase, we wished to find common ACO2 gene allozymes, functional polymorphisms that might be associated with susceptibility to human genetic diseases. We looked for ACO2 allozymes by DNA sequencing and genotyping in a population of 217 subjects, many of which had idiopathic Parkinson's disease (IPD). We studied patients with IPD because this movement disorder is thought to arise from defects in neuronal iron and energy metabolism, two properties with which aconitase is involved. Furthermore, reports of associations between alleles of the CYP2D6 locus (nearby on 22q13) and IPD, although inconsistent, indicated that an IPD susceptibility locus might be in strong linkage disequilibrium with CYP2D6. We found three functionally silent single nucleotide polymorphisms (SNPs) present in transcribed sequences that exist in similar frequencies in IPD patients and healthy controls. These ACO2 SNPs are in linkage disequilibrium with each other, providing evidence for distinct ACO2 haplotypes. We have, as yet, not detected polymorphisms that would lead to ACO2 allozymes, nor have we observed differences in ACO2 isoform prevalence or distribution in our population of IPD patients and controls. We conclude it is unlikely that polymorphism in the ACO2 gene or post-translational modification of the enzyme predispose to IPD.
authors.affiliation: Ernest Gallo Clinic, Research Center, University of California, San Francisco, San Francisco General Hospital, Building 1, Room 101, 1001 Potrero Avenue, San Francisco, CA 94110, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Mirel
authors.forename: K
authors.initials: K
authors.lastname: Marder
authors.forename: J
authors.initials: J
authors.lastname: Graziano
authors.forename: G
authors.initials: G
authors.lastname: Freyer
authors.forename: Q
authors.initials: Q
authors.lastname: Zhao
authors.forename: R
authors.initials: R
authors.lastname: Mayeux
authors.forename: K C
authors.initials: KC
authors.lastname: Wilhelmsen
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D005796:Genes; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007525:Isoelectric Focusing; D007527:Isoenzymes / Q000235:genetics*; D015810:Linkage Disequilibrium; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D013378:Substantia Nigra / Q000201:enzymology
chemical_list: D018076:DNA, Complementary; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D007501:Iron; D000154:Aconitate Hydratase