Steroid 21-Hydroxylase (P450c21) Naturally Occurring Mutants I172N, V281L and I236N/V237E/M239K Exert a Dominant Negative Effect on Enzymatic Activity when Co-expressed with the Wild-type Protein

Steroid 21-hydroxylase deficiency is the major cause of congenital adrenal hyperplasia, an autosomic recessive disorder that affects the synthesis of aldosterone and cortisol. The disease presents a wide spectrum of clinical phenotypes as a result of the combination of different mutant alleles. Due to the adrenal-specific expression of the enzyme, the study of the functional effect of different mutations is only possible through in vitro expression studies. Determination of the functional effect of independent mutations does not always result in clear phenotype-genotype correlations, particularly in those patients with different mutations in the two alleles (compound heterozygotes). In this study we show that co-expression of the mutant proteins I172N, V281L or I236N/V237E/M239K with the wild-type enzyme resulted in an apparent dominant negative effect on the enzymatic activity of the latter, while co-expression with the mutant enzyme R356W does not show this effect.