Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

Abstract

The HLA-linked human steroid 21-hydroxylase gene CYP21B and its closely homologous pseudogene CYP2JA are each normally located centromeric to a fourth component of complement (C4) (1). Although clinically heterogeneous, the disorder is always characterized by accumulation of 17-hydroxyprogesterone and by excessive androgen production, which, in the classical form of the disorder, results in masculinization ofthe external genitalia in affected female newborns.In addition, -70% ofclassical 21-OH deficiency patients show an inability to conserve dietary sodium ("salt-wasting") as a consequence of parallel deficiency in aldosterone production. The disorder maps within the class III region of the HLA complex on the short arm of chromosome 6, and molecular genetic investigations have revealed that most normal haplotypes contain, in addition to a functional 21-OH gene, CYP21B, a pseudogene, CYP21A, which shows 97% sequence homology to the functional gene. The CYP21A and CYP21B loci are positioned -=2 kilobases (kb) centromeric to the duplicated fourth component of complement (C4) genes, C4A and C4B, respectively (see Fig. 1), and the extant organization of these genes is presumed to reflect tandem duplication of an ancestral compound DNA unit -30 kb long and containing a single 21-OH gene and a single C4 gene (2, 3). Because of C4 gene length heterogeneity (4), the repeat units may be short (ca. 26 kb in length) or long (ca. 33 kb).The tandemly repeated organization of the 21-OH and C4 genes has been considered to facilitate gene deletion and addition events by unequal crossover mechanisms. Although the existence of haplotypes with variable numbers of C4 and 21-OH genes has been inferred by indirect short-range restriction mapping and complement C4 allotyping analyses, confirmation of the copy number variation has only recently been obtained by direct long-range restriction mapping approaches (5-7). Such studies have shown that gene expansion and contractions are frequent in the 21-OH/C4 gene cluster. Also, the size variation of haplotype-specific long-range restriction fragments that span the array of 21-OH and C4 genes is always consistent with integral numbers of the ca. 30-kb repeat units. Consequently, a considerable amount of circumstantial evidence has been accumulated in favor of the involvement of unequal crossover in the 21-OH/C4 gene cluster. In the present report, we present direct evidence for the occurrence of unequal crossover in this chromosomal region: a 21-OH deficiency patient has inherited a maternal haplotype that, as a result of meiotic recombination, has a ca. 30-kb de novo deletion that eliminates the functional CYP21B gene and a companion C4B gene.

Isolation and phylogeny of novel cytochrome P450 genes from tunicates (Ciona spp.): A CYP3 line in early deuterostomes?

“…There is precedent for recombination between tandemly duplicated CYPs (Sinnott et al, 1990;Pascoe et al, 1992;Goldstone and Stegeman, in press), suggesting the possibility of gene conversion here.…”

A Revised Evolutionary History of the CYP1A Subfamily: Gene Duplication, Gene Conversion, and Positive Selection

“…This astounding abundance has, of course, arisen primarily through gene duplication. Tandem duplication arrays are common among CYPs, as are documented cases of inter-paralog recombination (Sinnott et al, 1990;Pascoe et al, 1992).…”

The chimeric CYP21P/CYP21 gene and 21-hydroxylase deficiency

“…There have been various studies (White et al 1988;Sinnott et al 1990;Levo and Partanen 1997;Koppens et al 2000) indicating hybrid genes with the 30-kb deletion between CYP21P and CYP21 genes in Caucasians. Several studies (Lee et al 2002;Lee et al 2003a) have shown that there are three distinct chimeric CYP21P/CYP21s in the CYP21 gene in the ethnic Chinese population in Taiwan.…”