Five novel mutations in CYP11B2 gene detected in patients with aldosterone synthase deficiency type I: Functional...

Aldosterone synthase deficiency (ASD) is an important differential diagnosis of diseases associated with salt wasting in early infancy.

The objective of this study was to investigate the molecular basis for the disorder by (1) molecular genetic analysis in the CYP11B2 from patients suffering from ASD type I. (2) Functional characterization of the missense mutant gene products. (3) Structural simulation of the missense mutations.

Patient 1 was a homozygous carrier of a novel mutation located in exon 4 causing a premature stop codon (p.W260X). Patient 2 was analyzed to be compound heterozygous for two novel mutations: The first was an insertion mutation (p.G206WfsX51), and the second was a deletion mutation (p.L496SfsX169). Two siblings (patients 3 and 4) were compound heterozygous carriers of two novel missense mutations (p.S315R, p.R374W). The expression studies of the mutant proteins in COS-1 cells showed a complete absence of CYP11B2 activity of p.S315R and p.R374W mutants for the conversion of 11-deoxycorticosterone to aldosterone. A 3-D model of CYP11B2 p.S315R and p.R374W indicated a change of the hydrogen bond network which might explain the cause of the dysfunction.

We have identified the first CYP11B2 gene defects in two Polish families associated with phenotypes of ASD type I. Analysis of the enzymatic function as a complementary procedure to genotyping revealed data for understanding the clinical phenotype of ASD. Molecular modeling of the mutated enzyme provided a rational basis for understanding the changed activities of the mutant proteins.