TY - JOUR
T1 - Two novel mutations in CYP11B1 and modeling the consequent alterations of the translated protein in classic congenital adrenal hyperplasia patients
AU - Abbaszadegan, Mohammad Reza
AU - Hassani, Soolmaz
AU - Vakili, Rahim
AU - Saberi, Mohammad Reza
AU - Baradaran-Heravi, Alireza
AU - A'Rabi, Azadeh
AU - Hashemipour, Mahin
AU - Razzaghi-Azar, Maryam
AU - Moaven, Omeed
AU - Baratian, Ali
AU - Ahadian, Mitra
AU - Keify, Fatemeh
AU - Meurice, Nathalie
N1 - Funding Information:
Acknowledgments This study was supported by a Grant from Mashhad University of Medical Sciences (#86426).
PY - 2013/8
Y1 - 2013/8
N2 - Mutations in the 11β-hydroxylase (CYP11B1) gene are the second leading cause of congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by adrenal insufficiency, virilization of female external genitalia, and hypertension with or without hypokalemic alkalosis. Molecular analysis of CYP11B1 gene in CAH patients with 11β-hydroxylase deficiency was performed in this study. Cycle sequencing of 9 exons in CYP11B1 was performed in 5 unrelated families with 11β-hydroxylase deficient children. Three-dimensional models for the normal and mutant proteins and their affinity to their known substrates were examined. Analysis of the CYP11B1 gene revealed two novel mutations, a small insertion in exon 7 (InsAG393) and a small deletion in exon 2 (DelG766), and three previously known missense mutations (T318M, Q356X, and R427H). According to docking results, the affinity of the protein to its substrates is highly reduced by these novel mutations. DelG766 has more negative impact on the protein in comparison to InsAG393. The novel mutations, InsAG393 and DelG766, change the folding of the protein and disrupt the enzyme's active site as it was measured in the protein modeling and substrate binding analysis. Molecular modeling and sequence conservation were predictive of clinical severity of the disease and correlated with the clinical diagnosis of the patients.
AB - Mutations in the 11β-hydroxylase (CYP11B1) gene are the second leading cause of congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by adrenal insufficiency, virilization of female external genitalia, and hypertension with or without hypokalemic alkalosis. Molecular analysis of CYP11B1 gene in CAH patients with 11β-hydroxylase deficiency was performed in this study. Cycle sequencing of 9 exons in CYP11B1 was performed in 5 unrelated families with 11β-hydroxylase deficient children. Three-dimensional models for the normal and mutant proteins and their affinity to their known substrates were examined. Analysis of the CYP11B1 gene revealed two novel mutations, a small insertion in exon 7 (InsAG393) and a small deletion in exon 2 (DelG766), and three previously known missense mutations (T318M, Q356X, and R427H). According to docking results, the affinity of the protein to its substrates is highly reduced by these novel mutations. DelG766 has more negative impact on the protein in comparison to InsAG393. The novel mutations, InsAG393 and DelG766, change the folding of the protein and disrupt the enzyme's active site as it was measured in the protein modeling and substrate binding analysis. Molecular modeling and sequence conservation were predictive of clinical severity of the disease and correlated with the clinical diagnosis of the patients.
KW - CYP11B1
KW - Congenital adrenal hyperplasia
KW - Mutation
KW - Prenatal diagnosis
KW - Protein modeling
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U2 - 10.1007/s12020-012-9861-2
DO - 10.1007/s12020-012-9861-2
M3 - Article
C2 - 23345044
AN - SCOPUS:84881188519
SN - 1355-008X
VL - 44
SP - 212
EP - 219
JO - Endocrine
JF - Endocrine
IS - 1
ER -