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

2006 ◽  
Vol 154 (6) ◽  
pp. 859-864 ◽  
Author(s):  
A Luczay ◽  
D Török ◽  
A Ferenczi ◽  
J Majnik ◽  
J Sólyom ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Plasma Renin ◽  
Hydroxylase Deficiency ◽  
Laboratory Findings ◽  
Specific Pcr ◽  
Cyp21 Gene ◽  
Significant Difference ◽  
Allele Specific ◽  
21 Hydroxylase Deficiency

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.

scholarly journals High frequency of Q318X mutation in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in northeast Brazil

2009 ◽  
Vol 53 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Viviane C. Campos ◽  
Rossana M. C. Pereira ◽  
Natália Torres ◽  
Margaret de Castro ◽  
Manuel H. Aguiar-Oliveira
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
High Frequency ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Specific Pcr ◽  
Frequent Mutations ◽  
Allele Specific ◽  
Activity Screening ◽  
21 Hydroxylase Deficiency ◽  
Allele Specific Pcr

OBJETIVES: Deficiency of 21-hydroxylase is the most common form of congenital adrenal hyperplasia (CAH-21OH). The aim of this study was to determine, by allele-specific PCR, the frequency of microconversions of the CYP21A2, in sixteen patients with the classical forms and in 5 patients with the nonclassical (NC) form of CAH-21OH and correlate genotype with phenotype. METHODS: Genotypes were classified into 3 mutation groups (A, B and C), based on the degree of enzymatic activity. Screening for 7 microconversions by allele-specific PCR diagnosed 74.3% (n=26) of the 35 unrelated alleles. RESULTS: The most frequent mutations were Q318X (25.7%), V281L (17.1%), I2 Splice (14.3%), I172N (14.3%), and R356W (14.3%). Genotype was identified in 57.1% of the patients. We observed correlation between genotype and phenotype in 91.7% of the cases. CONCLUSION: The highest frequency for Q318X (25.7%) when compared to other studies may reflect individual sample variations in this Northeastern population.

scholarly journals Comprehensive and Cost-Effective Strategy for Genetic Screening of Congenital Adrenal Hyperplasia (CAH) in India

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A499-A499
Author(s):  
Lavanya Ravichandran ◽  
Sophy Korula ◽  
H S Asha ◽  
Deny Varghese ◽  
R Parthiban ◽  
...  
Keyword(s):  
Cost Effective ◽  
Compound Heterozygous ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Specific Pcr ◽  
Targeted Ngs ◽  
Allele Specific ◽  
Long Range Pcr ◽  
21 Hydroxylase Deficiency ◽  
Allele Specific Pcr

Abstract Background: With substantial challenges in molecular analysis of 21 hydroxylase deficiency and lack of studies in extended panel of genes implicated in CAH, genetic diagnosis is largely unavailable and unaffordable in India. Therefore, we aim to develop a cost-effective screening strategy in CAH using Allele Specific PCR and Targeted Next-Generation Sequencing (NGS). Methods: Long range PCR and restriction digestion were utilized to specifically amplify the CYP21A2 gene whereas multiplex PCR was used to amplify CYP11B1, CYP17A1, CYP19A1 and POR genes. In house developed Allele Specific PCR (ASPCR) for 8 hotspot mutations in CYP21A2 gene and targeted NGS for five genes was carried out. The results were validated using Sanger sequencing and MLPA. Results: Of the 50 patients suspected for 21 hydroxylase deficiency, 64% (n=32) were of Salt Wasting phenotype (SW), 30% (n=15) with Simple Virilizing (SV) phenotype and 6% (n=3) of the study population were suspected for non-classical (NC) CAH. The mutation positive rate of ASPCR was 86% (n=43). Seven patients carried more than two biallelic mutations indicating smaller gene conversions. The predominant mutation identified among the study subjects was I2G splice variant in SW phenotype (38%) and I172N in the SV phenotype (41%). Based on the Long range PCR amplification and restriction digestion we identified one patient with large gene conversion and one patient with large 30kb deletion. These results were confirmed with MLPA. Additionally, utilizing the Targeted NGS we identified five patients with CYP21A2 variants (two patients with novel variants c.1274G>T, c.17_18delTG and two other variants in three patients - c.1451G>C, c.143A>G). We also identified a CYP19A1:c.1142A>T gene variant in a patient who was initially suspected for 21 hydroxylase deficiency. Out of six patients with 11 beta hydroxylase deficiency four patients were positive for homozygous CYP11B1 variants (c.1201-1G>A, c.1200 + 1delG, c.412C>T) and two patients with compound heterozygous variants (c.1024C>T and c.1012dupC, c.623G>A and c.412C>T). Discussion: Utilizing the novel allele specific PCR followed by NGS we identified a total of 96% (48/50) of 21 hydroxylase deficiency patients with homozygous or compound heterozygous mutations and 2% (2/50) were positive for single heterozygous variant in CYP21A2 gene. ASPCR followed by multigene targeted NGS assay for genetic screening in CAH has shown to be a sensitive and specific strategy established in a clinical setting. To best of our knowledge this is the most cost-effective and comprehensive multigene screening carried out in India.

Association of +505A>G Polymorphism at TAFI Gene with Recurrent Miscarriage in Iranian Women

2021 ◽  
Author(s):  
Razieh Alivand ◽  
Fatemeh Abdi ◽  
Mahmood Dehghani-Ashkezari ◽  
Hossein Neamatzadeh ◽  
Sedigheh Ekraminasab
Keyword(s):  
Recurrent Miscarriage ◽  
Iranian Women ◽  
Specific Pcr ◽  
Study Results ◽  
Significant Difference ◽  
Fibrinolysis Inhibitor ◽  
History Of ◽  
Allele Specific ◽  
Allele Specific Pcr ◽  
Control Study

Background: Recurrent miscarriage (RM) is one of the major problems of public health globally. The thrombin-activatable fibrinolysis inhibitor (TAFI) gene is a plasma zymogen that regulates both fibrinolysis and inflammation. Genetic variants within TAFI gene are presumed to be associated with development of RM. This case-control study aimed to investigate the association of TAFI +505A>G polymorphism with RM in Iranian women referred to Meybod Genetic Center. Methods: Fifty women with RM (at least 2 miscarriages) and 50 healthy women with no history of miscarriage or other fertility complications were participated in this study. The TAFI +505A>G polymorphism was genotyped by allele specific PCR (AS-PCR) assay. Results: The mean age of cases with RM and controls was 27.25 ± 4.31 and 28.42 ± 3.22 years, respectively. The frequency of GG genotype and G allele was 0.00% in patients and controls. There was no significant difference between RM cases and controls in terms of +505A>G genotypes and alleles. Conclusion: This study results indicated that there was no significant relationship between the TAFI +505A>G polymorphism and RM risk in Iranian women. However, further rigorous, studies with a larger sample size and different ethnicity are necessary to confirm our findings.

scholarly journals CRP Gene Polymorphism and Their Risk Association With Type 2 Diabetes Mellitus

2019 ◽  
Vol 7 (1) ◽  
pp. 33-37
Author(s):  
Hakim Bahlok Jebur ◽  
Mirza Masroor ◽  
Hafiz Ahmad ◽  
Naushad Ahmad Khan ◽  
Juheb Akther ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gene Polymorphism ◽  
Inflammatory Marker ◽  
Genotype Distribution ◽  
Reactive Protein ◽  
Specific Pcr ◽  
Increased Risk ◽  
Significant Difference ◽  
Allele Specific

BACKGROUND: C-reactive protein (CRP) is an inflammatory marker associated with T2DM, obesity, insulin resistance, and cardiovascular disease. AIM: The present study evaluates the association of CRP +1059 G/C polymorphism of the CRP gene in 100 T2D cases and 100 healthy controls. METHODS: Present study was done by allele specific PCR method to study the CRP gene polymorphism in study subjects. RESULTS: Study found that CRP (+1059 G/C) genotype distribution among case and controls was found to be significant (p=0.001), Higher CRP C allele frequency (0.16) was observed compared to controls (0.04). CRP +1059 GC and CC had 2.72 (1.12-6.61), 20.56 (1.16-362.1) risk for T2D. It has been observed, HTN, Obesity, Smoking and alcoholism was found to be associated with increased risk of T2D, and a significant difference was observed in biochemical parameters. CONCLUSION: Study concluded that CRP gene polymorphism was found to be associated with risk of Type 2 Diabetes and risk was linked with heterozygosity and mutant homozygosity. Hypertension, Obesity, Smoking and alcoholism increases the risk of occurrence of Type 2 Diabetes.

Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency

1995 ◽  
Vol 5 (2) ◽  
pp. 126-130 ◽  
Author(s):  
Benoit Barbat ◽  
Any Bogyo ◽  
Marie-Charles Raux-Demay ◽  
Frédéarique Kuttenn ◽  
Joelle Boué ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Hydroxylase Deficiency ◽  
Cyp21 Gene ◽  
21 Hydroxylase Deficiency

scholarly journals Association between Genetic Polymorphism and Risk of von Willebrand Disease in Pakistan

2017 ◽  
Vol 2017 ◽  
pp. 1-5
Author(s):  
Najma Arshad ◽  
Syed Kashif Nawaz ◽  
Riffat Iqbal ◽  
Muhammad Arshad ◽  
Farhana Musheer ◽  
...  
Keyword(s):  
Von Willebrand Disease ◽  
Allelic Association ◽  
Specific Pcr ◽  
Allele Specific ◽  
Von Willebrand ◽  
Control Association ◽  
Association Design ◽  
Willebrand Factor ◽  
Allele Specific Pcr

von Willebrand disease (VWD) is an inherited, genetically and clinically heterogeneous hemorrhagic disorder. The most common cause of this disease is mutation in the gene that encodes protein von Willebrand factor (VWF) which is responsible for blood clotting. The current study was designed to investigate the role of genetic polymorphisms with the onset of VWD in population of Pakistan. Three exonic variants (c.3445T>C; c.4975C>T; c.7603C>T) from VWF gene were used for the genotyping purpose. The current study employed a case-control association design involving 43 VWD patients and 100 healthy controls from Pakistani population. The genetic reason of VWD was investigated using the allele specific PCR. The significant (P<0.05) allelic association was found between all three exonic variants and VWD. The CT genotype of these variants was noticed to be associated with significantly higher risk of VWD [odds ratio (95% CI): 14.7 (4.546–47.98), 26.71 (7.281–97.98), and 21.5 (5.806–80.01) for c.3445T>C, c.4975C>T, and c.7603C>T, resp.] while genotypes CC (c.4975C>T) and TT (c.3445T>C and c.7603C>T) were having protective effect against the disease. However, replicated studies are needed for elaborating the role of these SNPs.

scholarly journals Hormonal evaluation and mutation screening for steroid 21-hydroxylase deficiency in patients with unilateral and bilateral adrenal incidentalomas

2002 ◽  
pp. 349-355 ◽  
Author(s):  
A Patocs ◽  
M Toth ◽  
C Barta ◽  
M Sasvari-Szekely ◽  
I Varga ◽  
...  
Keyword(s):  
Mutation Screening ◽  
Tumor Formation ◽  
Adrenal Incidentalomas ◽  
Hydroxylase Deficiency ◽  
Similar Frequency ◽  
Specific Pcr ◽  
Large Gene ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Hormonal Evaluation

OBJECTIVE: The aims of the present study were (a) to examine the occurrence of 21-hydroxylase gene (CYP21) mutations in patients with unilateral and bilateral adrenal incidentalomas and (b) to correlate the results of mutation screening with hormonal parameters of 21-hydroxylase deficiency. DESIGN: The frequency of the eight commonly occurring CYP21 mutations in blood DNA samples of 19 patients with bilateral, as well as in blood and tumoral tissue DNA samples of 31 patients with unilateral adrenal incidentalomas, was determined. In all patients, hormonal evaluation for 21-hydroxylase deficiency was performed using measurements of basal and ACTH-stimulated plasma 17-hydroxyprogesterone (17-OHP) concentrations. METHODS: Blood and tumoral DNA samples were analyzed by allele-specific PCR for the detection of the eight commonly occurring CYP21 mutations (deletion/large gene conversion, intron 2 splicing, Ile172Asn, exon 6 cluster, Val281Leu, Leu307insT, Gln318Stop and Arg356Trp mutations). Plasma 17-OHP concentrations were measured by radioimmunoassay. RESULTS: Of the 19 patients with bilateral adrenal incidentalomas, one patient had homozygous (Val281Leu) and three patients had heterozygous germline CYP21 mutations (Val281Leu in two cases and Arg356Trp in one case). Heterozygous germline CYP21 mutations were also detected in five of the 31 patients with unilateral adrenal incidentalomas (Ile172Asn in three cases and Val281Leu in two cases). Mutation screening of tumoral DNA in unilateral incidentalomas showed the presence of corresponding germline mutations but no additional somatic mutations were found. ACTH-stimulated plasma 17-OHP concentrations were above 1500 ng/dl in all patients with bilateral incidentalomas who had homozygous and heterozygous CYP21 mutations, but heterozygous carriers with unilateral incidentalomas had highly variable ACTH-stimulated plasma 17-OHP levels (between 111 and 1705 ng/dl). CONCLUSIONS: These results suggest a similar frequency of germline CYP21 mutations in patients with bilateral and unilateral adrenal incidentalomas (21.1% and 16.1% respectively). Therefore, it cannot be ruled out that, in at least some patients, CYP21 mutations may play a role in the pathomechanism of bilateral and unilateral adrenal incidentalomas. However, the lack of clear association of CYP21 mutations with increased ACTH-stimulated plasma l7-OHP response, especially in patients with unilateral incidentalomas, suggests that the effect of CYP21 mutations on adrenocortical tumor formation may also involve mechanism(s) independent of ACTH-induced changes in 17-OHP secretion.

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