Two novel mutations in CYP11B1 and modeling the consequent alterations of the translated protein in classic congenital adrenal hyperplasia patients.
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.
Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences (MUMS), 9196773117, Mashhad, Iran. abbaszadeganmr@mums.ac.ir
Mohammad Reza
MR
Abbaszadegan
Soolmaz
S
Hassani
Rahim
R
Vakili
Mohammad Reza
MR
Saberi
Alireza
A
Baradaran-Heravi
Azadeh
A
A'rabi
Mahin
M
Hashemipour
Maryam
M
Razzaghi-Azar
Omeed
O
Moaven
Ali
A
Baratian
Mitra
M
Ahadian
Fatemeh
F
Keify
Nathalie
N
Meurice
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005190:Family; D006801:Humans; D008297:Male; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D014176:Protein Biosynthesis; D013252:Steroid 11-beta-Hydroxylase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D013252:Steroid 11-beta-Hydroxylase