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

Abstract

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder mainly caused by defects in the 21-hydroxylase gene (CYP21A2), coding for the enzyme 21-hydroxylase (21-OH). About 95% of the mutations arise from gene conversion between CYP21A2 and the inactive pseudogene CYP21A1P: only 5% are novel CYP21A2 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.L122P, p.Q481X, and p.E161X) in 3 Italian patients with CAH: the fourth mutation (p.M150R) 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.M150R mutation affected the activity to a minor extent, associated with NC CAH. CYP21A2 genotyping and functional characterization of each disease-causing mutation has relevance both for treatment and genetic counseling to the patients.

• Authors: A Massimi, M Malaponti, L Federici, D Vinciguerra, M L Manca Bitti, A Vottero, L Ghizzoni, M Maccarrone, M Cappa, S Bernardini, O Porzio
• Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme (Horm Metab Res) Vol. 46 Issue 7 Pg. 515-20 (Jun 2014) ISSN: 1439-4286 [Electronic] Germany
• PMID: 24799024 (Publication Type: Case Reports, Journal Article)
• Copyright: © Georg Thieme Verlag KG Stuttgart · New York.

Chemical References

• Mutant Proteins
• Steroid 21-Hydroxylase

Topics

• Adrenal Hyperplasia, Congenital (enzymology, genetics)
• Amino Acid Sequence
• Animals
• Blotting, Western
• COS Cells
• Child
• Chlorocebus aethiops
• Female
• Genotype
• Humans
• Infant, Newborn
• Italy
• Male
• Molecular Sequence Data
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Phenotype
• Protein Structure, Secondary
• Sequence Alignment
• Steroid 21-Hydroxylase (chemistry, genetics)