title: 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.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Massimi
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Malaponti
authors.affiliation: Department of Experimental and Clinical Sciences, Ce.S.I. Center of -Excellence on Aging, University of Chieti G. d'Annunzio, Chieti, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Federici
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Vinciguerra
authors.affiliation: Pediatric Diabetology and Endocrinology Unit, Policlinico Tor Vergata, Rome, Italy.
authors.forename: M L
authors.initials: ML
authors.lastname: Manca Bitti
authors.affiliation: Departments of Pediatrics, University of Parma, Parma, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vottero
authors.affiliation: Division of Endocrinology, Diabetology, and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ghizzoni
authors.affiliation: Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Endocrinology and Diabetology Unit and Research Laboratory, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cappa
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bernardini
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Porzio
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D013255:Steroid 21-Hydroxylase