Characterisation of three novel CYP11B1 mutations in classic and non-classic 11β-hydroxylase deficiency

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.

Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

“…There are up to 13 mutations associated with NC 11βOHD in the literature (Table 2) [32,38,62,[83][84][85]. The degree of enzyme activity compromise associated with NC 11βOHD is similar to that seen in NC 21OHD (20-50%) [14].…”

“…There is significant variability in BMI in patients with classic and NC 11βOHD [32,38,84,85,103]. Similarly, in 21OHD increased BMI has been reported in some [12,[104][105][106][107][108][109][110][111][112][113][114], but not all studies [25,98,115,116].…”

Genetics of Congenital Adrenal Hyperplasia

“…70,74 Novel mutations for both subtypes are being discovered routinely. 70,75,76 3. 17α-hydroxylase deficiency 17α-hydroxylase deficiency (17-OHD) (OMIM 202110) results from a defective CYP17A1 and accounts for approximately 1% of all CAH cases.…”

Chimeric CYP11B2 / CYP11B1 causing 11β-hydroxylase deficiency in Chinese patients with congenital adrenal hyperplasia

“…CYP11B1 and CYP11B2 are tandemly arranged, located 45 kb apart, on the long arm of chromosome 8. The underlying genetic causes of 11-OHD are primarily missense, nonsense, small deletion, small insertion and splice site mutations [4][5][6][7] in CYP11B1, with very few patients harboring CYP11B2/CYP11B1 chimeras arising from unequal crossing over between the two genes during meiosis [8][9][10]. In those rare cases, at least one chromatid contains the chimeric gene containing the 5 0 sequence of CYP11B2 and the 3 0 sequence of CYP11B1, but lacking wild-type CYP11B1 and CYP11B2 genes.…”