Balkan Journal of Medical Genetics

INTRON 2 SPLICE MUTATION AT CYP21 GENE IN PATIENTS WITH CONGENITAL ADRENAL HYPERPLASIA IN THE REPUBLIC OF MACEDONIA
Anastasovska V, Kocova M
*Corresponding Author: Mirjana Kocova, Department of Endocrinology and Genetics, University Children’s Clinic, Vodnjanska 17, 1000 Skopje, Republic of Macedonia; Tel.: +389-70-242-694; Fax: +389-23-129-027; E-mail: mirjanakocova@yahoo.com
page: 27

INTRODUCTION

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders of adrenal steroidogenesis and characterized by impaired activity of an enzyme required for cortisol biosynthesis [1]. Congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency is traditionally classed as a classic form with severe enzyme deficiency and prenatal onset of virilization; females present ambiguous genitalia at birth and in both sexes virilization continues postnatally, and a non classical form with mild enzyme deficiency and postnatal onset of premature adrenarche and pubarche in children, virilization in young women, and variable symptoms in young men. The classic form is further divided into the salt-wasting form (SW) with a severe defect in aldosterone biosynthesis, which leads to renal inability to conserve sodium and a simple virilizing (SV) form with apparently normal aldosterone biosynthesis [2-5]. The severe classical form occurs in one in 10,000 to 15,000 Caucasians [6]. The milder non classical CAH occurs in ~1 in 1,700 in the general population [5]. Based on newborn screening data, the carrier frequency of CAH in the general population is estimated to be 1 in 55 [7]. More than 95% of cases of CAH are caused by steroid 21-hydroxylase deficiency [6]. The structural gene, CYP21, for the adrenal cytochrome P450 specific for steroid 21-hydroxylation (P450c21) is 3.2 kb long and contains 10 exons. A CYP21 gene’s 2 kb transcript encodes a polypeptide of 494 or 495 amino acids. This variation results from the polymorphism length in exon 1, where a tandem repeat number may comprise (CTG)4 or (CTG)5 [8]. The CYP21 and a pseudogene (CYP21P, CYP21A1P) are located at the 3’ terminus of each of the two genes encoding the fourth component of complements C4A and C4B within the HLA genes, in a DNA segment ~30 long, in which a tandem duplication probably occurred during evolution [9]. Because of the high homology and tandem-repeat organization, this gene cluster is subject to a high frequency of recombination events, which can lead either to unequal crossover during meiosis, which can produce a wide variety of rearrangements depending on the breakpoint, or large or small gene conversion events that transfer deleterious mutations in the CYP21P gene to the CYP21 gene [10-13]. However, apart from gene deletions and large gene conversions, nine such pseudogenederived mutations account for about 95% of all affected CYP21 alleles in different ethnic groups, while ~5% are de novo mutations which did not arise in the pseudogene [6]. There is a good relationship between genotype and clinical disease presentation but a combination of CYP21 mutations can cause different phenotypes [14-16]. The IVSII- 656 (C/A>G), the 8 bp frameshift deletion at codon 111-113, the thymidine insertion at codon 306 (p.Phe306+t), the nonsense mutation at codon 318 (p.Gln318X), and the single base substitution at codon 356 (p.Arg356Trp), result in complete inactivation of CYP21, and are found in the severe classical SW form of CAH [17-19]. Here, we present results of direct molecular detection of a CYP21 IVS-II mutation, in which the normal polymorphic C or A at nucleotide 655 has been converted to G, in 41 Macedonian patients with different clinical forms of CAH.

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