Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B.
We mapped crossover sites in chimeric, recombinant CYP21 genes from six patients with salt-losing congenital adrenal hyperplasia (CAH). Nucleotide sequences unique to the CYP21A pseudogene or to the active CYP21B gene were mapped using gene-specific restriction sites and oligonucleotide hybridizations. Each chimeric CYP21 gene in the CYP21-deletion linked haplotypes contained sequences near the 5' end that were characteristic of CYP21A and only a single transition from sequences of CYP21A to those of CYP21B at the 3' end. The transitions all occurred within either of two discrete regions (+470 to +999 and +1375 to +1993). All eight chimeric CYP21 genes coupled with HLA-Bw47 in five unrelated patients had the CYP21A-CYP21B sequence transition within the same gene region (+1375 to +1993). One of the three other "CYP21B deletion" haplotypes (HLA-B7) had a sequence transition within this same region, while in the other two haplotypes (HLA-B61 and HLA-B18) the transition occurred between base pairs +470 and +999. By contrast, both CYP21 genes in a haplotype containing a gene conversion of CYP21B to CYP21A contained apparent transitions between sequences of CYP21A and CYP21B. We conclude that a single, unequal crossingover between the CYP21A and the CYP21B genes yields deletion of the active CYP21 gene and salt-losing CAH and that these crossingovers do not occur randomly within the CYP21 genes of our patients.
Donohoue
P A
PA
Division of Pediatric Endocrinology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
Jospe
N
N
Migeon
C J
CJ
Van Dop
C
C
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D001483:Base Sequence; D015139:Blotting, Southern; D002678:Chimera; D002872:Chromosome Deletion; D003434:Crossing Over, Genetic; D005260:Female; D005785:Gene Conversion; D005796:Genes; D015235:HLA-B Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D015345:Oligonucleotide Probes; D011544:Pseudogenes; D015183:Restriction Mapping; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics*
D015235:HLA-B Antigens; D015345:Oligonucleotide Probes; D013250:Steroid Hydroxylases; D013255:Steroid 21-Hydroxylase