scholarly journals Meta analysis of variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2.

2021 ◽  
Author(s):  
Mayara Jorgens Prado ◽  
Rodrigo Ligabue-Braun ◽  
Arnaldo Zaha ◽  
Maria Lucia Rosa Rossetti ◽  
Amit V Pandey
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
In Silico ◽  
Meta Analysis ◽  
Genetic Disorders ◽  
In Silico Prediction ◽  
Adrenal Hyperplasia ◽  
Single Nucleotide Variants ◽  
Mild Phenotype ◽  
The Impact

Context: CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia cases (CAH), a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provides critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Objective: Analyze the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of the CYP21A2. Methods: SNVs of the CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of the CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. Results: SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews' correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). Conclusion: From our analysis, we identified four predictors of CYP21A2 pathogenicity with good performance. These results can be used for future analysis to infer the impact of uncharacterized SNVs' in CYP21A2.

scholarly journals Meta Analysis of Variant Predictions in Congenital Adrenal Hyperplasia Caused by Mutations in CYP21A2

2021 ◽  
Author(s):  
Mayara Jorgens Prado ◽  
Rodrigo Ligabue-Braun ◽  
Arnaldo Zaha ◽  
Maria Lucia Rosa Rossetti ◽  
Amit Pandey
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
In Silico ◽  
Meta Analysis ◽  
Genetic Disorders ◽  
In Silico Prediction ◽  
Adrenal Hyperplasia ◽  
Single Nucleotide Variants ◽  
Mild Phenotype ◽  
The Impact

Context: CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia cases (CAH), a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provides critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Objective: Analyze the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of the CYP21A2. Methods: SNVs of the CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of the CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. Results: SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews' correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). Conclusion: From our analysis, we identified four predictors of CYP21A2 pathogenicity with good performance. These results can be used for future analysis to infer the impact of uncharacterized SNVs' in CYP21A2.

scholarly journals Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia

2017 ◽  
Vol 176 (4) ◽  
pp. 405-411 ◽  
Author(s):  
Nayananjani Karunasena ◽  
Daniel N Margetson ◽  
Greg Neal ◽  
Martin J Whitaker ◽  
Richard JM Ross
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Phase 1 ◽  
Immediate Release ◽  
Modified Release ◽  
Adrenal Hyperplasia ◽  
Fed State ◽  
Free Cortisol ◽  
Rate Of Absorption ◽  
The Impact

Background We developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm. Subjects and methods In vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone. Results In vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer Tmax (fed vs fasted: 6.75 h vs 4.5 h, P = 0005) and lower Cmax (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71–85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0t for fed/fasted was 108.33% (102.30–114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58–126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0–125.0%: Geo LSmean ratio (CI) for AUC0t 112.73% (105.33–120.65%). Conclusions Gastric pH ≤6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone.

scholarly journals Nonsense variant of NR0B1 causes hormone disorders associated with congenital adrenal hyperplasia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Da-Bei Fan ◽  
Li Li ◽  
Hao-Hao Zhang
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Energy Homeostasis ◽  
Hypogonadotropic Hypogonadism ◽  
Chinese Family ◽  
Orphan Nuclear Receptor ◽  
Inherited Disease ◽  
Adrenal Hyperplasia ◽  
Infancy And Early Childhood ◽  
Disordered Energy

AbstractCongenital adrenal hyperplasia (CAH) is a rare X-linked recessive inherited disease that is considered a major cause of steroidogenesis disorder and is associated with variants or complete deletion of the NR0B1 gene. The DAX-1 protein (encoded by NR0B1) is a vertebrate-specific orphan nuclear receptor and is also a transcriptional factor for adrenal and reproductive development. CAH usually causes adrenal insufficiency in infancy and early childhood, leading to hypogonadotropic hypogonadism in adulthood; however, few adult cases have been reported to date. In this study, we examined a Chinese family with one adult patient with CAH, and identified a putative variant of NR0B1 gene via next-generation sequencing (NGS), which was confirmed with Sanger sequencing. A novel nonsense variant (c.265C>T) was identified in the NR0B1 gene, which caused the premature termination of DAX-1 at residue 89 (p.G89*). Furthermore, mutant NR0B1 gene displayed a partial DAX-1 function, which may explain the late pathogenesis in our case. Additionally, qPCR revealed the abnormal expression of four important genes identified from ChIP-seq, which were associated with energy homeostasis and steroidogenesis, and were influenced by the DAX-1 mutant. In addition, hormone disorders can be caused by DAX-1 mutant and partially recovered by siRNA of PPARGC1A. Herein, we identified a novel nonsense variant (c.265C>T) of NR0B1 in a 24-year-old Chinese male who was suffering from CAH. This mutant DAX-1 protein was found to have disordered energy homeostasis and steroidogenesis based on in vitro studies, which was clinically consistent with the patient’s phenotypic features.

In silico prediction, LC-HRMS/MS analysis, and targeted/untargeted data-mining workflow for the profiling of phenylfentanyl in vitro metabolites

Talanta ◽  
2021 ◽  
pp. 122740
Author(s):  
Annagiulia Di Trana ◽  
Pietro Brunetti ◽  
Raffaele Giorgetti ◽  
Enrico Marinelli ◽  
Simona Zaami ◽  
...  
Keyword(s):  
Data Mining ◽  
In Silico ◽  
In Silico Prediction ◽  
Ms Analysis

scholarly journals Digit ratio (2D:4D) and congenital adrenal hyperplasia (CAH): Systematic literature review and meta-analysis

2020 ◽  
Vol 126 ◽  
pp. 104867 ◽  
Author(s):  
Gareth Richards ◽  
Wendy V. Browne ◽  
Ezra Aydin ◽  
Mihaela Constantinescu ◽  
Gideon Nave ◽  
...  
Keyword(s):  
Literature Review ◽  
Congenital Adrenal Hyperplasia ◽  
Systematic Literature Review ◽  
Meta Analysis ◽  
Digit Ratio ◽  
Adrenal Hyperplasia

scholarly journals Phycobilins as Potent Food Bioactive Broad-Spectrum Inhibitors Against Proteases of SARS-CoV-2 and Other Coronaviruses: A Preliminary Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Brahmaiah Pendyala ◽  
Ankit Patras ◽  
Chandravanu Dash
Keyword(s):  
Binding Affinity ◽  
Broad Spectrum ◽  
In Silico ◽  
Research Area ◽  
Therapeutic Drug ◽  
Inhibitor Activity ◽  
Current Vaccine ◽  
Mutant Strains ◽  
The Impact

In the 21st century, we have witnessed three coronavirus outbreaks: SARS in 2003, MERS in 2012, and the ongoing pandemic coronavirus disease 2019 (COVID-19). The search for efficient vaccines and development and repurposing of therapeutic drugs are the major approaches in the COVID-19 pandemic research area. There are concerns about the evolution of mutant strains (e.g., VUI – 202012/01, a mutant coronavirus in the United Kingdom), which can potentially reduce the impact of the current vaccine and therapeutic drug development trials. One promising approach to counter the mutant strains is the “development of effective broad-spectrum antiviral drugs” against coronaviruses. This study scientifically investigates potent food bioactive broad-spectrum antiviral compounds by targeting main protease (Mpro) and papain-like protease (PLpro) proteases of coronaviruses (CoVs) using in silico and in vitro approaches. The results reveal that phycocyanobilin (PCB) shows potential inhibitor activity against both proteases. PCB had the best binding affinity to Mpro and PLpro with IC50 values of 71 and 62 μm, respectively. Also, in silico studies with Mpro and PLpro enzymes of other human and animal CoVs indicate broad-spectrum inhibitor activity of the PCB. As with PCB, other phycobilins, such as phycourobilin (PUB), phycoerythrobilin (PEB), and phycoviolobilin (PVB) show similar binding affinity to SARS-CoV-2 Mpro and PLpro.

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