Background: Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11β-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH.
Aim: The aim of the study was to study the functional consequences of three novel CYP11B1 gene mutations (p.His125Thrfs*8, p.Leu463_Leu464dup and p.Ser150Leu) detected in patients suffering from 11OHD and to correlate this data with the clinical phenotype.
Methods: Functional analyses were done by using a HEK293 cell in vitro expression system comparing WT with mutant P450c11 activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein.
Results: Two mutations (p.His125Thrfs*8 and p.Leu463_Leu464dup) detected in patients with classic 11OHD showed a complete loss of P450c11 activity. The mutation (p.Ser150Leu) detected in a patient with non-classic 11OHD showed partial functional impairment with 19% of WT activity.
Conclusion: Functional mutation analysis enables the correlation of novel CYP11B1 mutations to the classic and non-classic 11OHD phenotype respectively. Mutations causing a non-classic phenotype show typically partial impairment due to reduced maximum reaction velocity comparable with non-classic mutations in 21-hydroxylase deficiency. The increasing number of mutations associated with non-classic 11OHD illustrate that this disease should be considered as diagnosis in patients with otherwise unexplained hyperandrogenism.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1530/EJE-13-0737 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
High clinical utility of long-read sequencing for precise diagnosis of congenital adrenal hyperplasia in 322 probands.
Hum Genomics
January 2025
Department of Endocrine and Metabolic Diseases, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.
Background: The molecular genetic diagnosis of congenital adrenal hyperplasia (CAH) is very challenging due to the high homology between the CYP21A2 gene and its pseudogene CYP21A1P.
Methodology: This study aims to assess the clinical efficacy of targeted long-read sequencing (T-LRS) by comparing it with a control method based on the combined assay (NGS, Multiplex ligation-dependent probe amplification and Sanger sequencing) and to introduce T-LRS as a first-tier diagnostic test for suspected CAH patients to improve the precise diagnosis of CAH.
Results: A large cohort of 562 participants including 322 probands and 240 family members was enrolled for the perspective (96 probands) and prospective study (226 probands).
Cracking the code of aldosterone synthase deficiency: bridging genetics and biochemistry: a case report.
Lab Med
December 2024
Department of Pediatrics, AIIMS Patna, Patna, Bihar, India.
Objective: Aldosterone synthase deficiency (ASD) is a rare autosomal recessive inherited disease with an overall clinical phenotype of failure to thrive, vomiting, severe dehydration, hyperkalemia, and hyponatremia. Mutations in the CYP11B2 gene encoding AS are responsible for the occurrence of ASD. Defects in CYP11B2 gene have only been reported in a limited number of cases worldwide.
View Article and Find Full Text PDFTargeted long-read sequencing identifies missing pathogenic variant in unsolved 11β-hydroxylase deficiency.
BMC Endocr Disord
October 2024
Department of Endocrinology and Metabolism, Cheeloo College of Medicine, Qilu Hospital, Shandong University, Jinan, 250012, P.R. China.
Article Synopsis
- 11β-hydroxylase deficiency (11β-OHD) is a genetic disorder that results from mutations in the CYP11B1 gene and is a common cause of congenital adrenal hyperplasia, affecting the hormonal balance in affected individuals.
- The study investigated two siblings from a Chinese family with 11β-OHD, using various advanced genetic testing methods to identify the specific mutations affecting them.
- The researchers discovered two pathogenic variants in the CYP11B1 gene, highlighting the effectiveness of using long-range PCR-based next-generation sequencing and target long-read sequencing for accurate genetic diagnosis.
Application and insights of targeted next-generation sequencing in a large cohort of 46,XY disorders of sex development in Chinese.
Biol Sex Differ
September 2024
Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China.
Purpose: 46,XY disorders of sex development (46,XY DSD) are characterized by incomplete masculinization of genitalia with reduced androgenization. Accurate clinical management remains challenging, especially based solely on physical examination. Targeted next-generation sequencing (NGS) with known pathogenic genes provides a powerful tool for diagnosis efficiency.
View Article and Find Full Text PDFFirst-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor.
Clin Transl Sci
August 2024
Mineralys Therapeutics, Radnor, Pennsylvania, USA.
Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!