A Novel 9-bp Insertion Detected in Steroid 21-hydroxylase Gene (CYP21A2): Prediction of Its Structural and Functional Implications by Computational Methods

Overview

Journal J Biomed Sci

Publisher Biomed Central

Specialty Biology

Date 2009 Mar 11

PMID 19272182

Citations 3

Authors

Sudhisha Dubey

Susan Idicula-Thomas

Mohammad Anwaruddin

Chinnaraj Saravanan

R Raveendra Varma

Anurupa Maitra

Affiliations

Soon will be listed here.

Abstract

Background: Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH). Detection of underlying mutations in CYP21A2 gene encoding steroid 21-hydroxylase enzyme is helpful both for confirmation of diagnosis and management of CAH patients. Here we report a novel 9-bp insertion in CYP21A2 gene and its structural and functional consequences on P450c21 protein by molecular modeling and molecular dynamics simulations methods.

Methods: A 30-day-old child was referred to our laboratory for molecular diagnosis of CAH. Sequencing of the entire CYP21A2 gene revealed a novel insertion (duplication) of 9-bp in exon 2 of one allele and a well-known mutation I172N in exon 4 of other allele. Molecular modeling and simulation studies were carried out to understand the plausible structural and functional implications caused by the novel mutation.

Results: Insertion of the nine bases in exon 2 resulted in addition of three valine residues at codon 71 of the P450c21 protein. Molecular dynamics simulations revealed that the mutant exhibits a faster unfolding kinetics and an overall destabilization of the structure due to the triple valine insertion was also observed.

Conclusion: The novel 9-bp insertion in exon 2 of CYP21A2 genesignificantly lowers the structural stability of P450c21 thereby leading to the probable loss of its function.

Citing Articles

Novel variants of CYP21A2 in Vietnamese patients with congenital adrenal hyperplasia.

Chi D, Tran T, Nguyen D, Luong L, Le P, Ta M Mol Genet Genomic Med. 2019; 7(5):e623.

PMID: 30816000 PMC: 6503067. DOI: 10.1002/mgg3.623.

Steered molecular dynamics simulation of the binding of the bovine auxilin J domain to the Hsc70 nucleotide-binding domain.

Xue Y, Zhou L, Sun Y, Li H, Jones G, Song Y J Mol Model. 2017; 23(11):320.

PMID: 29063205 DOI: 10.1007/s00894-017-3453-2.

Prenatal diagnosis of steroid 21-hydroxylase-deficient congenital adrenal hyperplasia: Experience from a tertiary care centre in India.

Dubey S, Tardy V, Chowdhury M, Gupta N, Jain V, Deka D Indian J Med Res. 2017; 145(2):194-202.

PMID: 28639595 PMC: 5501051. DOI: 10.4103/ijmr.IJMR_329_16.

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