A novel 9-bp insertion detected in steroid 21-hydroxylase gene (CYP21A2): prediction of its structural and functional implications by computational methods

J Biomed Sci. 2009 Jan 8;16(1):3. doi: 10.1186/1423-0127-16-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Hyperplasia, Congenital / enzymology
  • Adrenal Hyperplasia, Congenital / genetics
  • Alleles
  • Amino Acid Sequence
  • Base Sequence
  • Computational Biology / methods*
  • DNA Mutational Analysis*
  • Exons
  • Female
  • Humans
  • Infant
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Insertional*
  • Protein Conformation
  • Steroid 21-Hydroxylase / chemistry
  • Steroid 21-Hydroxylase / genetics*
  • Steroid 21-Hydroxylase / metabolism


  • Steroid 21-Hydroxylase