This thesis is aimed at understanding the relationship between the genetic defects that cause steroid 21-hydroxylase deficiency and the clinical phenotype, and the molecular mechanisms that create these mutations in the CYP21 gene, in a patient population from the Netherlands. Soon after the discovery of the CYP21 gene and the nearby CYP21P pseudogene, a picture emerged of great variability in the arrangement of these genes on chromosome 6p21.31. Some of these variants constitute genetic defects that cause steroid 21-hydroxylase deficiency. The study's initial objective was therefore to obtain an image of that variability by charting the layout of the genetic environment of the CYP21 gene in steroid 21-hydroxylase deficiency patients and in the general population. Two genetic mechanisms that are fundamental to the evolution of the genome, and especially the MHC, are also instrumental in generating the variability in this region: - simultaneous deletion and duplication of genes by unequal crossover, and: - non-reciprocal sequence transfer between genes by gene conversion. A major point of attention in this thesis is how these mechanisms create alleles that carry steroid 21-hydroxylase deficiency. For genetic analysis of CYP21 defects, it is often assumed that a chromosome either carries a CYP21 gene, or has a CYP21 deletion. Chapter 7 demonstrates that this assumption is not without risk: chromosomes with two CYP21 genes in tandem are found in the general population at a frequency equal to or higher than steroid 21-hydroxylase deficiency alleles. Since one of the two CYP21 genes is defective on such chromosomes, PCR-based mutation analysis without haplotyping can lead to erroneous assignment of carrier status.

, , , , ,
Büller, Prof. Dr. H.A. (promotor), Degenhart, Prof. Dr. H.J. (promotor)
H.A. Büller (Hans) , H.J. Degenhart (Herman)
Erasmus University Rotterdam
Erasmus MC: University Medical Center Rotterdam

Koppens, P. F. J. (2002, June 26). Molecular genetics and epidemiology of steroid 21-hydroxylase deficiency. Origin of disease-causing mutations.. Retrieved from