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

A. Massimi, M. Malaponti, L. Federici, D. Vinciguerra, M. L. Manca Bitti, A. Vottero, L. Ghizzoni, M. Maccarrone, M. Cappa, S. Bernardini, O. Porzio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)515-520
Number of pages6
JournalHormone and Metabolic Research
Volume46
Issue number7
DOIs
Publication statusPublished - 2014

Keywords

  • 21-hydroxylase
  • congenital adrenal hyperplasia (CAH)
  • CYP21A2
  • genotype-phenotype
  • molecular modeling

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

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