The combination of a novel 2 bp deletion mutation and p.D63H in CYP11B1 cause congenital adrenal hyperplasia due to steroid 11β-hydroxylase deficiency

Endocr J. 2016;63(3):301-10. doi: 10.1507/endocrj.EJ15-0433. Epub 2016 Jan 22.

Abstract

Deficiency of steroid 11β-hydroxylase activity occurs in 5-8% of patients with congenital adrenal hyperplasia (CAH). The aim of the current study was to identify mutations in the CYP11B1 gene of a patient with CAH due to deficiency of steroid 11β-hydroxylase activity, and to study the functional and structural consequences of these mutations. A molecular genetic analysis of the CYP11B1 gene in this patient and her parents identified a known missense mutation g.5194G>C (p.D63H) and a novel 2 bp deletion mutation (g.9525_9526delCT, corresponding to p.L380V…R420X) in the patient. In vitro expression studies in COS7 cells revealed a decreased 11β-hydroxylase activity in the p.D63H mutant to 2.0±0.8% and in the p.L380V…R420X mutant to 0.2±2.2% for the conversion of 11-deoxycortisol to cortisol. Three dimensional homology models for the normal and mutant proteins were built by using the recently published x-ray structure of the human CYP11B2 as a template. Presumably, the g.9525_9526delCT mutation in CYP11B1 resulted in a truncated protein with a misfolded C-terminal domain that could not efficiently bind heme iron, substrate, and adrenodoxin and had lost its biochemical function. In summary, CAH due to steroid 11β-hydroxylase deficiency can be attributed to both the novel deletion mutation (g.9525_9526delCT, corresponding to p.L380V…R420X) and known missense mutation (g.5194G>C corresponding to p.D63H) in CYP11B1.

Publication types

  • Case Reports

MeSH terms

  • Adrenal Hyperplasia, Congenital / genetics*
  • Adrenal Hyperplasia, Congenital / metabolism
  • Adrenal Hyperplasia, Congenital / physiopathology
  • Adult
  • Amino Acid Substitution
  • Animals
  • COS Cells
  • China
  • Chlorocebus aethiops
  • DNA Mutational Analysis
  • Female
  • Frameshift Mutation*
  • Gene Deletion*
  • Humans
  • Menorrhagia / etiology
  • Menorrhagia / physiopathology
  • Mutation, Missense*
  • Parents
  • Pedigree
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Severity of Illness Index
  • Steroid 11-beta-Hydroxylase / chemistry
  • Steroid 11-beta-Hydroxylase / genetics*
  • Steroid 11-beta-Hydroxylase / metabolism
  • Structural Homology, Protein

Substances

  • Recombinant Proteins
  • Steroid 11-beta-Hydroxylase

Supplementary concepts

  • Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency