Balkan Journal of Medical Genetics

DETECTION OF MUTATIONS IN THE CYP21A2 GENE: GENOTYPE-PHENOTYPE CORRELATION IN SLOVENIAN COUPLES WITH CONCEIVING PROBLEMS
Stangler Herodež Š1,*, Fijavž L2, Zagradišnik B1, Kokalj Vokač N1,2
*Corresponding Author: Dr. Špela Stangler Herodež, Laboratory of Medical Genetics, University Clinical Centre Maribor, Ljubljanska ulica 5, 2000 Maribor, Slovenia. Tel: +386-2-321-27-37. Fax: +386-2-321-27-55. E-mail: spela.sh@ukc-mb.si
page: 25

INTRODUCTION

The World Health Organization (WHO) estimates that 10.0-15.0% of couples in the Western World develop issues regarding fertility. In addition, we can estimate that nearly 50.0% of couples with infertility have an underlying genetic abnormality [1]. Mutation in the CYP21A2 gene results in a defficient 21-hydroxilase (21-OH) enzyme, which in turn leads to diminished aldosterone and cortysole production. Contrarily, the production of testosterone and dihydrotestosterone increases [2,3]. Congenital adrenal hyperplasia is a hereditary autosomal recessive disease. A defective 21-OH enzyme is responsible for 90.0% of disrupted steroid hormone production. The 21-OH catalyzes the conversion of progesterone and 17-hydroxyprogesterone (17-OHP) into 11-deoxycorticosterone (11-DOC) and 11-deoxycortisol. The enzyme is coded by the CYP21A2 gene at position 6p21.3 [1,4]. Genes involved in steroidogenesis usually comprise 7 to 9 exons but the CYP21A2 gene has 10 exons. In humans, there are two genes associated with coding 21-OH, both located on 6p21.3, on a region 35 kb in length in the major histocompatibility complex. The first of two is a disfunctional pseudogene (CYP21A1 or CYP21P), the second is a functional gene (CYP21A2 or CYP21). The pseudogene encodes an enzyme, nonfunctional due to the frameshift and occurence of a premature stop codon [5]. Although we cannot establish the phenotype only from the genetic profile, there are certain associations between the two. Patients with a detected mutation in the CYP21A2 gene are divided into groups by the severity of the mutation on 21-OH [6]. Clinical findings associated with the phenotype are not always proportional to the degree of disfunction of 21-OH. We assume there are other genes involved in the manifestation of symptoms. There is marked concordance between genotype and phenotype in patients with mild or severe manifestation of congenital adrenal hyperplasia (CAH) [7,8]. Nevertheless, the most common manifestations are virilizing effects, clinically evident as hirsutism or androgenic alopecia. Oligomenorrhea or amenorrhea and ultrasound-evident polycystic ovaries may also be present [2,9,10]. Reduced fertility in female patients with CAH is often associated with excessive androgen levels. Adrenal androgens directly inhibit aromatase activity in granulosa cells of the ovary, thus indirectly hindering foliculogenesis. The high androgen levels result in gonadotropin-releasing hormone (GnRH), inhibition, leading to anovulation [10,11]. Thankfully, with glucocorticoid replacement therapy of patients with classical CAH, females mature into adults, so the focus has shifted to infertility treatment [2]. These patients suffer not only from salt wasting, they also have concomitant excessive androgens, excessive progesterone, post-reconstructive surgery states, PCOS, ovarian adrenal rest tumors and various psychosexual factors [1,5,11-14]. In our study, we presumed that the mutations c.290-13A/C>G, p.I172N, p.P30L and p.V281L in the CYP21A2 gene are associated with infertility and influence clinical and laboratory parameters of women with UFP. For this purpose, we compared genetic profiles of couples with UFP with genetic profiles of healthy controls (HCs). Furthermore, we have also analyzed associations between mutations in the CYP21A2 gene and various clinical and laboratory parameters.

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