Mutations in Steroid 21-Hydroxylase (CYP21)

Abstract

The inherited inability to synthesize cortisol is termed congenital adrenal hyperplasia. More than 90% of cases are caused by 21-hydroxylase deficiency. This syndrome is characterized by signs of androgen excess and often mineralocorticoid deficiency. Steroid 21-hydroxylase (P450c21) is a microsomal enzyme expressed in the adrenal gland that catalyzes conversion of 17-hydroxyprogesterone and progesterone to 11-deoxycortisol and deoxycorticosterone respectively. In man, this enzyme is encoded by the CYP21 (CYP21B) gene which is located in the HLA major histocompatibility complex along with a pseudogene, CYP21P (CYP21A). Mutations in CYP21 causing congenital adrenal hyperplasia are almost all generated by recombinations between CYP21 and CYP21P. These recombinations either delete CYP21 or transfer deleterious mutations from CYP21P to CYP21, a process termed apparent gene conversion. The degree of enzymatic compromise caused by each mutation is correlated with the clinical severity of the deficiency observed in patients carrying that mutation.

Embryonic expression of tenascin‐X suggests a role in limb, muscle, and heart development

“…A similar observation was made in the cloning of a mouse TN-X cDNA fragment and suggests a gene conversion event whereby sequences from 21A are mutated to the corresponding sequences in 21B or vice versa. This phenomenon is well described in the human P450c21 locus (Morel and Miller, 1991;White et al, 1994). Recombination may have occurred in the animals from which either the mouse cDNA or gene sequences were derived.…”

“…In humans, 21-hydroxylase deletions are a relatively common cause of congenital adrenal hyperplasia (Speiser et al, 1992) but no deletion extending into the TN-X gene has been described. Gene conversion is the most common mechanism of 21-hydroxylase deficiency in humans (Morel and Miller, 1991;White et al, 1994) and the occurrence of similar recombinational events in the murine P450c2UTN-X genes suggests this is a generalized feature of the locus. Yet in both circumstances the coding region of TN-X is spared, again suggesting an essential function.…”

Tracing past population migrations: genealogy of steroid 21-hydroxylase (CYP21) gene mutations in Finland

“…8 Assuming that there has been no substantial change in the carrier rate in the past, many of the early settlers of Finland may have carried a defective CYP21 gene. In addition, the frequency of de novo mutations in CYP21 is high (1-2% of affected alleles), 14 increasing further the mutational spectrum. Our finding of genetic heterogeneity in CYP21 deficiency is of general importance for genetic studies of common disorders.…”

“…With the exception of a few novel sporadic point mutations reported, only two types of mutation are found in CYP21 deficiency: 14 large deletions leading to a nonfunctional CYP21P/CYP21 fusion gene, and gene conversion type of mutation where a part of the functional gene has been replaced by a pseudogene-derived deleterious segment. As the pseudogene carries only a limited number of mutations, 14 identical but obviously independently borne mutations in the CYP21 gene have been detected in all populations studied so far. Thus, haplotype information is essential for analysis of origins of CYP21 mutations.…”

Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?

“…Val281Leu mutation results in an enzyme with 50% of normal activity when 17-OHP is the substrate, but only 20% of normal activity for progesterone. 14 Lack of detectable mutations in the entire CYP21 gene has also been reported in patients suffering from CAH. 15 Independent studies on Italian, Spanish and French patients report frequencies of alleles without mutations ranging between 11 and 22%, and that the finding is more common in the non-classical form of the disease.…”