CYP21A2 mutations in women with polycystic ovary syndrome (PCOS).

The question of the contribution of CYP21A2 heterozygosity to the development of polycystic ovary syndrome (PCOS) has repeatedly been raised in the literature. The available data, however, do not offer a satisfactory answer. The discrepancy must be attributed, primarily, to the small number of subjects in the various studies, the type of selected phenotype, and the number of searched mutations. The aim of the study was to define the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS. We searched for 14 molecular defects of the CYP21A2 gene in 197 PCOS women, employing allele specific PCR. Androgen levels were determined at baseline by appropriate methodology in the follicular phase. PCOS women with 17-hydroxyprogesterone (17OHP) basal values >2 ng/ml and/or post-ACTH >10 ng/ml were excluded. Appropriate controls were included. The frequency of the CYP21A2 heterozygous mutations in PCOS women and in controls was 7.6% and 5.9%, respectively [p-value (PCOS vs. controls): 0.663]. Homozygosity for CYP21A2 gene defects was not detected. In conclusion, the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS is not substantiated by our data. Moreover, 17-hydroxyprogesterone values of < 10 ng/ml post-ACTH exclude homozygosity of CYP21A2 mutations.

The spectrum of molecular defects of the CYP21 gene in the Hellenic population: variable concordance between genotype and phenotype in the different forms of congenital adrenal hyperplasia.

Defective steroid synthesis due to 21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia. Knowledge of the molecular defects causing 21-hydroxylase deficiency in different populations is of both theoretical and practical interest. The types and the relative frequencies of molecular defects and the correlation between the genotype and the phenotype were examined in the Hellenic population. We searched for deletions, conversions, and 11 of the most frequent mutations of the CYP21 gene by Southern blot and allele-specific PCR in 222 chromosomes from 111 unrelated subjects and their parents. The most frequent molecular defects were 1) in the salt wasting form, I(2) splice (42.9%), deletions and conversions (24.5%), and Q318stop (14.3%); 2) in the simple virilizing form, I172N (35.3%), I(2) splice (29.4%), and P30L (19.1%); and 3) in the nonclassical form, V281L (41.1%), P30L (21.4%), and P453S (14.3%). Compared with other populations, Greek patients had a higher frequency of Q318stop in the salt-wasting form, of P30L in both simple virilizing and nonclassical forms and of P453S in the nonclassical form. The concordance of genotype to phenotype in the total sample was 87%. However, the concordance rate was different in the three forms of the disease. Thus, complete concordance was detected in the genotypes predicting the salt-wasting phenotype, a slightly lower concordance (95.2%) was detected in the genotypes predicting the simple virilizing phenotype, and the lowest concordance (67.6%) was observed in genotypes predicting the nonclassical phenotype. In conclusion, the concordance between genotype and phenotype decreases as the severity of the disease diminishes. This should be taken into consideration in genetic counseling and antenatal intervention.

Genetic aspects of congenital adrenal hyperplasia.

Data related to genetics of congenital adrenal hyperplasia with emphasis on CYP21 gene defects are briefly outlined. Mutations of the StAR gene lead to impaired translocation of cholesterol from the outer mitochondrial membrane to the inner mitochondria, a rate limiting step in steroidogenesis in the adrenals and the gonads. The clinical picture is characterized by adrenal and gonadal insufficiency and sex reversal in XY individuals. Molecular defects of the CYP17 gene encoding 17alpha-hydroxylase can cause hypertension, impaired sexual maturation and impaired sexual differentiation in XY individuals. Molecular defects of the CYP11B1 gene lead to 11-hydroxylase deficiency, which is clinically expressed with virilization of the external genitalia of the female and precocious puberty in the male, as well as hypertension in both sexes. The HSD3beta1 and HSD3beta2 genes encode two isoenzymes (3betaHSDI and 3betaHSDII). The clinical picture results from either absence or diminished activity of type II 3betaHSD, resulting from mutations of the HSD3beta2 gene. The most frequent form of CAH (90% of all patients) is due to deletions, conversions or point mutations of the CYP21 gene, which encodes the enzyme 21-hydroxylase. There is a wide range of clinical expression primarily explained by the type of the molecular defect. The ratio of genotype to phenotype concordance varies in the different forms of the disease, the highest one being encountered in the non-classical form. Heterozygosity of CYP21 mutations may be expressed as premature pubarche.