Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency

Abstract

Objective: Congenital adrenal hyperplasia (CAH) shows a range of severity which is explained in part by the different mutations of the CYP21 gene. To better understand the incomplete concordance between genotype and phenotype in CAH the role of the sensitizing N363S polymorphism of the glucocorticoid receptor (GR) was examined in CAH patients. Design: CAH patients were screened for N363S. Laboratory findings and clinical characteristics of carriers and non-carriers were analyzed retrospectively. Methods: The CYP21 gene of 200 CAH patients was analyzed by allele-specific PCR. The GR gene was tested for N363S by PCR followed by restriction fragment length polymorphism. Antropometric data (height, weight), degree of intrauterine virilization, hormone concentrations (17-OH-progesterone, dehydroepiandrosterone (DHEA), aldosterone, testosterone, plasma renin activity), substitution doses and clinical course were analyzed. Results: The carrier frequency of N363S in CAH patients was equivalent to that of the general Hungarian population (6% vs 7.8%). Interestingly, none of the non-classical CAH (NC-CAH) patients were carriers of the polymorphism. Carrier girls had milder genital virilization than mutation-matched non-carrier controls. There was no significant difference between the carriers and non-carriers in either the substitution doses, the hormonal, or the auxiological parameters. Conclusions: The association of sensitizing the GR variant with impaired cortisol production in CAH might be compensatory in mild NC-CAH and may prevent severe intrauterine virilization in classical form. Although the exact role of N363S in extrauterine life should be further investigated, the consideration of certain genetic polymorphisms of CAH patients may lead to better, individualized therapeutic regimes.European Journal of Endocrinology 154 859-864

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

“…For the more frequent BclI polymorphism, we found 467 heterozygous and 127 homozygous samples. Genotypes were in HardyWeinberg equilibrium; allele frequencies (363S 2.6%; 23K 2.0%; BclI 36.1%) were comparable with those reported previously in Western European populations (8,9,12,13). Table 1 lists gestational age, birth weight, and age of the babies at the time blood samples for screening had been taken, showing no differences between genotype groups.…”

“…Background genetic factors such as individual androgen receptor (AR) sensitivity due to nCAG length polymorphisms within the AR gene have been suggested to explain parts of the phenotypical variability (7). Interestingly, genetically determined increased glucocorticoid receptor (GR) sensitivity in 363S-carriers of the GR N363S variant has recently been found to be associated with less severe virilization and lower 17-OHP levels in females at the time CAH was diagnosed clinically (8). We therefore speculated whether functional GR variants, by modulating the individual setpoint of the neonatal HPA-axis, might explain the wide range of 17-OHP levels observed in unaffected individuals.…”

Association of the GAA1013→GAG polymorphism of the insulin-like growth factor-1 receptor (IGF1R) gene with premature pubarche

“…Acting through IGF1R, IGF-1 augments steroidogenesis in both cultured human adrenal cells and fetal adrenocortical cells (11,41). With the observations that IGF-1 concentrations rise during childhood and that girls with PP have elevated IGF-1 concentrations, it has been speculated that IGF-1 plays a role in the initiation of adrenarche.…”

Szteroid-21-hidroxiláz-deficientia, a congenitalis adrenalis hyperplasia leggyakoribb oka

“…A de novo mutációk aránya 1-2% [20,21], tehát az esetek túlnyomó részében már a betegek egészséges szü-leiben is megtalálhatóak a kóroki mutációk heterozigóta formában. A különböző pontmutációk okozzák összes-ségében a 21-OHD-esetek többségét (2. táblázat, 2/B ábra), amelyek standard genetikai diagnosztikai módsze-rekkel jól vizsgálhatók [22,23]. Az egyes pontmutációk gyakorisága viszont általában alacsony, ezért a legtöbb-ször 2 különböző pontmutáció figyelhető meg a beteg 2 kromoszómáján (összetett heterozigótaság, compound heterozygosity).…”