Mechanism and consequences of the duplication of the human C4/P450c21/gene X locus.

Abstract

The adjacent C4 and P450c21 genes encode the fourth component of serum complement and steroid 21-hydroxylase respectively, and are tandemly duplicated in the human, murine, and bovine genomes. We recently cloned a cDNA for another duplicated gene, operationally termed X, which overlaps the 3' end of human P450c21 and has the opposite transcriptional orientation. Thus, the organization of the locus is 5'-C4A-21A-XA-C4B-21B-XB-3' (Y. Morel, J. Bristow, S. E. Gitelman, and W. L. Miller, Proc. Natl. Acad. Sci. USA 86:6582-6586, 1989). To determine how this locus was duplicated, we sequenced the DNA at the duplication boundaries and the 7 kb between P450c21A and C4B comprising the XA locus. The sequences located the duplication boundaries precisely and indicate that the duplication occurred by nonhomologous recombination. The boundaries are substantially different from those of the corresponding duplication in the mouse genome, suggesting that similar gene duplications may have occurred independently in ancestors of rodents and primates after mammalian speciation. Compared with XB, the XA gene is truncated at its 5' end and bears a 121-bp intragenic deletion causing a frameshift and premature translational stop signal. Nevertheless, XA is transcribed into a stable 2.6-kb polyadenylated RNA that is expressed uniquely in the adrenal gland.

Tenm, a Drosophila gene related to tenascin, is a new pair-rule gene.

“…Restrictin can promote cell adhesion of neural cells, but does not promote neurite extension (Rathjen et al, 1991). No functional data are available yet on the human tenascin-X gene, which is prominently expressed in fetal muscle and testis and at lower levels in fetal adrenal gland, kidney and lung (Gitelman et al, 1992;Bristow et al, 1993). However, it has been suggested that this gene has an essential function, since many cases of adrenal hyperplasia have been traced to gene deletions in close proximity to, but never within, the tenascin-like gene (Bristow et al, 1993).…”

Transcriptional Regulatory Elements of the Human Gene for Cytochrome P450c21 (Steroid 21-Hydroxylase) Lie within Intron 35 of the Linked C4B Gene

“…Human P450c21 is encoded by the CYP21B gene, which lies in a complex array of genes on chromosome 6p21.3. The human (8 -10), bovine (11,12), and rodent (13,14) genomes have duplicated CYP21A and CYP21B genes, but these duplications postdate mammalian speciation and have different duplication boundaries (15). Only the human 21B gene encodes P450c21, as the 21A gene carries three mutations that destroy the reading frame (8 -10).…”

“…1). The 5Ј ends (transcriptional start sites) of the human CYP21A and CYP21B genes lie only 2466 bp downstream from the polyadenylation sites of the corresponding C4A and C4B genes (15,18).…”

“…XB encodes the extracellular matrix protein tenascin-X (19 -22); XB-S is a truncated XB transcript that arises from a promoter within an intron of XB and encodes a protein of unknown function (23); XA is an expressed, truncated XB gene that carries an internal deletion and does not encode protein (15); YA-S, YA-L, YB-S, and YB-L are short (S) and long (L) alternately spliced transcripts that arise at or near the CYP21A and B transcriptional start sites but have a different exonic array and lack open reading frames (24); the ZA and ZB transcripts arise from promoters within intron 35 of the C4A and C4B genes and have the potential to encode a protein identical to the carboxyl-terminal 131 amino acids of C4 (25) (Fig. 1).…”

Modular Variations of the Human Major Histocompatibility Complex Class III Genes for Serine/Threonine Kinase RP, Complement Component C4, Steroid 21-Hydroxylase CYP21, and Tenascin TNX (the RCCX Module)

“…TNXA is a partially duplicated gene segment that corresponds to intron 32 to exon 45 of TNXB. In addition, there is a 120-bp deletion at exon 36-intron 36 that results in a frameshift mutation and premature termination of translation (30,40).…”