IDENTIFICATION OF THE CANDIDATE ALS2 GENE AT CHROMOSOME 2Q33 AS A HUMAN ALDEHYDE OXIDASE GENE

Denver, Tokyo, and Salt Lake City investigators recently published dif ferent complimentary deoxyribonucleic acid (cDNA) sequences for human liver xanthine dehydrogenase/xanthine oxidase (XD/XO). The gene encodi ng the Denver cDNA was subsequently linked to juvenile familial amyotr ophic lateral sclerosis (JFALS) at chromosome 2q33 and has been propos ed as the ALS2 locus, The present investigation was undertaken to eluc idate the differences between the three cDNA sequences, and we provide evidence that the Denver cDNA encodes aldehyde oxidase (AO): first, t he Denver cDNA sequence diverged significantly from the Tokyo and Salt Lake City cDNA sequences which were very similar; second, the deduced protein sequence from the Denver cDNA was very similar to the amino a cid sequence of purified rabbit liver AO protein; third, the deduced D enver protein sequence was 76% identical to the encoded 101 amino acid long peptides from partial cDNAs for rabbit and rat AO and 81.7% iden tical to 300 amino acids from an incomplete cDNA encoding bovine AO; f ourth, the Denver gene was expressed in liver, kidney, lung, pancreas, prostate, testes, and ovary while the Tokyo XD gene was expressed pre dominantly in liver and small intestine; fifth, the Denver gene was pr eviously mapped to chromosome 2q33 which is syntenic to the mouse AO l ocus on chromosome 1, Our results have revealed dramatic similarities in protein and DNA sequence in the human molybdenum hydroxylases, have uncovered unanticipated complexity in the human molybdenum hydroxylas e genes, and advance the potential for AO derived oxygen radicals in J FALS and other human diseases.