Functional and structural analysis of four novel mutations of CYP21A2 gene in italian patients with 21-hydroxylase deficiency.

[congenital adrenal hyperplasia]

Congenital adrenal hyperplasia (CAH ) is an autosomal recessive disorder mainly caused by defects in the 21 -hydroxylase gene (CYP 21 A 2 ), coding for the enzyme 21 -hydroxylase (21 -OH ). About 95 % of the mutations arise from gene conversion between CYP 21 A 2 and the inactive pseudogene CYP 21 A 1 P : only 5 % are novel CYP 21 A 2 mutations , in which functional analysis of mutant enzymes has been helpful to correlate genotype-phenotype . In the present study , we describe 3 novel point mutations (p .L 122 P , p .Q 481 X , and p .E 161 X ) in 3 Italian patients with CAH : the fourth mutation (p .M 150 R ) was found in the carrier state . Molecular modeling suggests a major impact on 21 -hydroxylase activity , and functional analysis after expression in COS -7 cells confirms reduced enzymatic activity of the mutant enzymes . Only the p .M 150 R mutation affected the activity to a minor extent , associated with NC CAH . CYP 21 A 2 genotyping and functional characterization of each disease-causing mutation has relevance both for treatment and genetic counseling to the patients .