Two novel mutations in CYP11B1 and modeling the consequent alterations of the translated protein in classic congenital adrenal hyperplasia patients

Abbaszadegan, M.R. and Hassani, S. and Vakili, R. and Saberi, M.R. and Baradaran-Heravi, A. and A'Rabi, A. and Hashemipour, M. and Razzaghi-Azar, M. and Moaven, O. and Baratian, A. and Ahadian, M. and Keify, F. and Meurice, N. (2013) Two novel mutations in CYP11B1 and modeling the consequent alterations of the translated protein in classic congenital adrenal hyperplasia patients. Endocrine, 44 (1). pp. 212-219.

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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. © 2013 Springer Science+Business Media New York.

Item Type: Article
Additional Information: cited By 9
Uncontrolled Keywords: 11beta hydroxysteroid dehydrogenase 1; glucocorticoid; hydrocortisone; mutant protein; prednisolone; spironolactone, 11beta hydroxylase deficiency; adolescent; adrenal insufficiency; adrenalectomy; article; autosomal recessive disorder; binding affinity; child; clinical article; congenital adrenal hyperplasia; disease severity; drug substitution; enzyme active site; enzyme deficiency; exon; gene deletion; gene insertion; gene mutation; human; hypertension; infant; male; missense mutation; molecular docking; nucleotide sequence; preschool child; priority journal; protein binding; protein folding; school child; virilization, Adolescent; Adrenal Hyperplasia, Congenital; Child; Child, Preschool; DNA Mutational Analysis; Family; Humans; Male; Models, Molecular; Molecular Docking Simulation; Mutation; Pedigree; Protein Biosynthesis; Steroid 11-beta-Hydroxylase
Subjects: WK Endocrine System
Depositing User: somayeh pourmorteza
Date Deposited: 19 May 2019 06:32
Last Modified: 19 May 2019 06:32

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