Congenital adrenal hyperplasia due to 11-hydroxylase deficiency--insights from two novel CYP11B1 mutations (p.M92X, p.R453Q).
BACKGROUND
Steroid 11-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Herein, we describe two novel CYP11B1 mutations (g659_660dupTG, p.M92X; g.4817G>A, p.R453Q) found in a patient diagnosed with classic 11OHD, after presenting with borderline elevated 17-hydroxyprogesterone concentrations in CAH newborn screening.


METHODS
A novel CYP11B1 variant (p.R453Q) identified in a patient with classic 11OHD was characterized employing a COS7 cell assay and a computational three-dimensional CYP11B1 model.


RESULTS
The in vitro expression analysis revealed an almost complete loss of function of p.R453Q. This finding was consistent with the clinical presentation of classic 11OHD as the patient was compound heterozygous for p.R453Q and a nonsense mutation (p.M92X) on the other allele. Inserting the p.R453Q mutation into our CYP11B1 model provided two potential explanations for the almost complete loss of enzyme activity. Firstly, the heme coordination is most likely disturbed. A second possibility could be an altered interaction with the redox partner adrenodoxin.


CONCLUSIONS
Results indicate that both novel mutations are disease-causing mutations. Proving the pathogenic effect of a missense sequence variation is of particular importance for clinical genetic counseling as this provides essential information on the prediction of recurrence risk and disease severity.
Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
Nils
N
Krone
Joachim
J
Grötzinger
Paul-Martin
PM
Holterhus
Wolfgang G
WG
Sippell
Hans-Peter
HP
Schwarz
Felix G
FG
Riepe
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008715:Methionine / Q000235:genetics; D008958:Models, Molecular; D020125:Mutation, Missense / Q000502:physiology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*; D014162:Transfection
D018698:Glutamic Acid; D001120:Arginine; D008715:Methionine; D013252:Steroid 11-beta-Hydroxylase