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Vol. 62, Issue 2, 320-325, August 2002
Department of Pediatrics, Birth Defects Research Center (R.N.H.,
K.A.H.) and Departments of Pharmacology and Toxicology (R.N.H.);
Medicine (J.F., K.S.); and Surgery (F.P.B.); Medical College of
Wisconsin, Milwaukee, Wisconsin
The flavin-containing monooxygenases (FMOs) are a family of five
microsomal enzymes important for the oxidative metabolism of
environmental toxicants, natural products, and therapeutics. With the
exception of FMO5, the FMO are encoded within a single gene cluster on
human chromosome 1q23-25. As part of the human genome effort, an
FMO-like gene, FMO6, was
identified between FMO3 and FMO2
(GenBank accession no. ALO21026). Sequence analysis of this
putative FMO family member revealed nothing that would a
priori argue against a functional gene and encoded protein. When
FMO6 expression was examined by reverse transcriptase
coupled polymerase chain reaction DNA amplification, transcripts were identified in 8 of 11 human liver samples, but 0 of 4 kidney biopsy samples. However, in all cases, the observed transcripts were shorter
than predicted. Sequence analysis revealed skipping of exon 4, exons 3 and 4, and/or the use of alternative splice donor or acceptor sites in
introns 3, 4, 6, and 8, resulting in nine unique transcripts. Based on
an analysis of possible open reading frames, none of these transcripts
would encode a functional FMO enzyme. Taking advantage of the high
sequence identity between FMO3 and FMO6,
it is posited that the loss of binding sites for the
serine-arginine-rich splicing factor protein family within exons 3 and
4 contributes to the exon skipping events, although the most commonly
observed alternative splice event results from a 21-bp insertion
immediately 3' to the predicted FMO6 intron 8 splice
acceptor site, diminishing the efficiency of this site.
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