ABUNDANT ADRENAL-SPECIFIC TRANSCRIPTION OF THE HUMAN P450C21A PSEUDOGENE

Human adrenal steroid 21-hydroxylase (P450c21) is encoded by the CYP21 A1 (21B) gene located in the class III region of the HLA locus. A tand emly duplicated gene designated CYP21A1P (21A), which lies 30 kilobase s upstream, contains several point mutations and an 8-base pair deleti on so that it cannot encode P450c21 protein; as a result, it is genera lly considered to be a pseudogene. We previously showed that two addit ional genes, XA and XB, lie on the opposite strand of DNA overlapping the 3'-ends of the 21A and 21B genes. We have now identified a third p air of duplicated overlapping genes in this locus, termed YA and YB, w hose transcriptional orientation is the same as 21A and 21B and opposi te to XA and XB. YA transcripts use the 21A promoter, have 5'-ends tha t are similar to 21B mRNA, and have approximately 10-20% of the abunda nce of 21B transcripts, but have unique 3'-ends. The YA gene encodes a 7.5-kilobase RNA that overlaps XA completely and a 3.0-kilobase RNA t hat excludes most of XA. The YB gene appears to be similar in size and organization to YA. The YA and YB genes extend beyond the limit of th e duplication in this locus; hence, their cDNAs are distinguishable by differences in their 3'-sequences. YA and YB transcripts are expresse d only in the fetal and adult adrenal glands, but their cDNAs do not c ontain a long open reading frame. Although the function of these genes is not yet clear, the complex genetic organization of three overlappi ng genes (21/X/Y) appears to be unique among higher eukaryotes. As YA transcription is initiated by the 21A 5'-flanking DNA and includes 21A sequences, the designation of 21A as a ''pseudogene'' merits reconsid eration.