MUTATION-HAPLOTYPE ANALYSIS OF STEROID 21-HYDROXYLASE (CYP21) DEFICIENCY IN FINLAND - IMPLICATIONS FOR THE POPULATION HISTORY OF DEFECTIVE ALLELES

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase def iciency is a common inherited defect of adrenal steroid hormone biosyn thesis. Unusually for genetic disorders, the majority of mutations cau sing CAH apparently result from recombinations between the CYP21 gene encoding the 21-hydroxylase enzyme and the closely linked, highly homo logous pseudogene CYP21P. The CYP21 and CYP21P genes are located in th e major histocompatibility complex class III region on chromosome 6p21 .3. We analyzed the mutations and recombination breakpoints in the CYP 21 gene and determined the associated haplotypes in 51 unrelated Finni sh families with CAH. They represent no less than half of all CYP21 de ficiency patients in Finland. The results indicate the existence of mu ltiple founder mutation-haplotype combinations in the population of Fi nnish CAH patients. The three most common haplotypes constituted half of all affected chromosomes; only one-sixth of the haplotypes represen ted single cases. Each of the common haplotypes was shown consistently to carry a typical CYP21 mutation and only in some cases was addition al variation observed. Surprisingly, comparisons with previous publish ed data revealed that several of the frequent mutation-haplotype combi nations in Finland are in fact also found in many other populations of patients of European origin, thus suggesting that these haplotypes ar e of ancient origin. This is in clear contrast to many reports, includ ing the present one, where a high frequency of de novo mutations in th e CYP21 gene has been reported. In addition, two unique sequence aberr ations in CYP21 (W302X and R356Q), not known to exist in the CYP21P ps eudogene, were detected.