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
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
(2014) 170, 697–706
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
22.214.171.124) 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
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