Expression of multiple catechol-o-methyltransferase (COMT) mRNA variants in human brain

Catechol-o-methyltransferase (COMT) is important for modulating dopamine levels, prefrontal cortex (PFC) function, and several psychiatric phenotypes. A single COMT mRNA has been described in human brain, which gives rise to membrane-bound (MB)- and soluble (S)-COMT proteins. In addition, we have recently described a novel COMT protein isoform in the human PFC, suggesting that there are more COMT gene products expressed than are currently appreciated. Therefore, we have investigated whether variant COMT mRNAs are present in human brain. We used reverse transcription-PCR (RT-PCR) to screen systematically for variant COMT mRNAs in human frontal cortex. Intron-spanning primers were used for exon-to-exon PCR reactions; additionally, specific primers were designed to sequences in the NCBI Aceview database. The identity of amplicons was confirmed by sequencing, and their regional distributions and 3' untranslated regions (UTRs) were characterised using RT-PCR. We detected 7 COMT variant mRNAs, resulting from both insertions and deletions within the known COMT brain transcript. Several of the variants alter the predicted coding sequence. Three of these variants correspond to sequences within the Aceview database and could be reliably amplified, while the remaining four do not correspond to any expressed sequence tags and were amplified only once. The regional distributions of these transcripts are described. The results demonstrate multiple COMT mRNAs in human brain, revealing an additional complexity to the biology of COMT. The alternate gene products may be of significant functional importance, and differentially impacted by polymorphisms within the COMT gene.