Abstract

Background: Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited

endocrine diseases. Steroid 11b-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.

European Journal of

Endocrinology

(2014) 170, 697–706

Introduction

Congenital adrenal hyperplasia (CAH), one of the

most common autosomal recessive inherited endocrine

diseases, is characterised by complete or partial

impairment of adrenal steroidogenesis (1, 2). Although

over 90% of cases of CAH are caused by 21-hydroxylase

deficiency, steroid 11b-hydroxylase (P450c11, EC

1.14.15.4) deficiency (11OHD) accounts for 5–8% of

cases, reflecting a frequency of w1:100 000–1:200 000

live births in non-consanguineous populations (3, 4, 5).

The 11b-hydroxylase belongs to the cytochrome

P450 system (P450c11) that facilitates the conversion of

11-deoxycortisol (S) to cortisol (F) and 11-deoxycorticosterone

(DOC) to corticosterone (B) in the mitochondria

of the adrenal cortex. 11OHD is characterised by deficient

European Journal of Endocrinology

Clinical Study

S Polat and others Three novel CYP11B1 mutations 170:5 697–706

www.eje-online.org
2014 European Society of Endocrinology

DOI: 10.1530/EJE-13-0737 Printed in Great Britain

Published by