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

doi:10.1055/s-0034-1371864

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2014; 46(07): 515-520
DOI: 10.1055/s-0034-1371864

Endocrine Care

Functional and Structural Analysis of Four Novel Mutations of CYP21A2 Gene in Italian Patients with 21-Hydroxylase Deficiency

Authors

A. Massimi

¹Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
M. Malaponti

¹Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
L. Federici

²Department of Experimental and Clinical Sciences, Ce.S.I. Center of Excellence on Aging, University of Chieti G. d’Annunzio, Chieti, Italy
D. Vinciguerra

¹Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
M. L. Manca Bitti

³Pediatric Diabetology and Endocrinology Unit, Policlinico Tor Vergata, Rome, Italy
A. Vottero

⁴Departments of Pediatrics, University of Parma, Parma, Italy
L. Ghizzoni

⁵Division of Endocrinology, Diabetology, and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy
M. Maccarrone

⁶Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy
M. Cappa

⁷Endocrinology and Diabetology Unit and Research Laboratory, Bambino Gesù Childrenʼs Hospital, Rome, Italy
S. Bernardini

¹Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
O. Porzio

¹Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy

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.

Key words

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

Volltext

Referenzen

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