title: 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 CYP21A are each normally located centromeric to a fourth component of complement (C4) gene, C4B and C4A, respectively, in an organization suggesting tandem duplication of a ca. 30-kilobase DNA unit containing a CYP21 gene and a C4 gene. Such an organization has been considered to facilitate gene deletion and addition events by unequal crossover between the tandem repeats. We have identified a steroid 21-hydroxylase [steroid, hydrogen-donor:oxygen oxidoreductase (21-hydroxylating), EC 1.14.99.10] deficiency patient who has a maternally inherited disease haplotype that carries a de novo deletion of a ca. 30-kilobase repeat unit including the CYP21B gene and associated C4B gene. This disease haplotype appears to have been generated as a result of meiotic unequal crossover between maternal homologous chromosomes. One of the maternal haplotypes is the frequently occurring HLA-DR3, B8, A1 haplotype that normally carries a deletion of a ca. 30-kilobase unit including the CYP21A gene and C4A gene. Haplotypes of this type may possibly act as premutations, increasing the susceptibility of developing a 21-hydroxylase deficiency mutation by facilitating unequal chromosome pairing.
authors.affiliation: University Department of Medical Genetics, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Sinnott
authors.forename: S
authors.initials: S
authors.lastname: Collier
authors.forename: C
authors.initials: C
authors.lastname: Costigan
authors.forename: P A
authors.initials: PA
authors.lastname: Dyer
authors.forename: R
authors.initials: R
authors.lastname: Harris
authors.forename: T
authors.initials: T
authors.lastname: Strachan
mesh_terms: D000312:Adrenal Hyperplasia, Congenital; D015139:Blotting, Southern; D002872:Chromosome Deletion; D003181:Complement C4 / Q000235:genetics; D003434:Crossing Over, Genetic; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D015342:DNA Probes; D005260:Female; D005796:Genes; D008040:Genetic Linkage; D006680:HLA Antigens; D006801:Humans; D008297:Male; D008540:Meiosis; D005810:Multigene Family; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D015183:Restriction Mapping; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D003181:Complement C4; D015342:DNA Probes; D006680:HLA Antigens; D004247:DNA; D013250:Steroid Hydroxylases; D013255:Steroid 21-Hydroxylase