Variations in the 3′UTR of theCYP21A2Gene in Heterozygous Females with Hyperandrogenaemia

Abstract

Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3′UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the ∗52C>T, ∗440C>T, and ∗443T>C in the 3′UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the ∗12C>T and ∗52C>T was identical in all heterozygous patients with the p.Gln318∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3′UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients.

Genotype Is Associated to the Degree of Virilization in Patients With Classic Congenital Adrenal Hyperplasia

“…According to genetic findings from previous studies as well as our present study, 17 different variants have been identified in the Greek-Cypriot population and are scattered throughout the entire coding sequence of the CYP21A2 gene (22, 32, 40, 42, 43). In the present study we identified nine different variants and the most frequent defect among the 36 tested alleles was the IVS2-13A/C>G (36.11%) followed by DelEx1-3 (19.44%) and a series of seven other less frequent mutations.…”

“…Currently, more than 200 mutations in the CYP21A2 gene have been described in several studies and there is a good correlation between the clinical phenotype and the patient genotypic findings (1, 21, 38–43). In general, our genotype-phenotype correlation was in accordance with previous studies and showed a positive predictive value for patients carrying mutations belonging to the null group (44–46).…”

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

“…Additionally, 3 children belonging to the SV group exhibited GnRH independent precocious puberty. At this time, more than 200 mutations in the CYP21A2 gene have been reported in numerous studies and there is a good concordance between the clinical phenotype and the patient genotypic findings [13,16,17,21,[37][38][39][40]. The genetic population profile of CAH and endocrinopathies in the Cypriot population is characterized by low consanguinity rates and by similarities to what is observed regarding these disorders in the Eastern Mediterranean countries [41,42].…”

“…Since 2007 our group has extensively studied the genetic implication of CYP21A2 in Cypriot patients with CAH. These included the true carrier frequency in the general population of Cyprus [10], the genotype-phenotype association with the various forms of CAH [14][15][16][17][18], the impact of heterozygosity in female patients with hyperandrogenemia [19,20], and the implication of variants in the untranslated 5′UTR region of the CYP21A2 gene [21]. In the present update, we present the molecular genetic features of the disease in patients of Cypriot descent over the last 11 years.…”

Reproductive health, obesity, and cardiometabolic risk factors among Samoan women

“…There may also be unique socio-cultural, genetic, and epigenetic factors associated with such reproductive traits, given the strong evolutionary advantage of high potential for successful conception, pregnancy, and child survival. Certainly our recent finding in 21st century Samoans of a novel missense mutation in the CREBRF gene enriched by natural selection, which is positively associated with adiposity but negatively associated with glucose and diabetes (Minster et al 2016), provides justification for conducting more detailed biocultural, including genetic, studies on reproductive health and phenotypes (Neocleous et al 2017; Cui et al 2015). The patterns of lower than expected menstrual irregularity and PCOS among Samoan women despite high adiposity, diabetes and androgen levels associated with the nutritional environmental changes requires more detailed research within an explicit population-specific human evolutionary reproductive biology and ecology framework.…”