title: The combination of a novel 2 bp deletion mutation and p.D63H in CYP11B1 cause congenital adrenal hyperplasia due to steroid 11β-hydroxylase deficiency.
abstract: Deficiency of steroid 11β-hydroxylase activity occurs in 5-8% of patients with congenital adrenal hyperplasia (CAH). The aim of the current study was to identify mutations in the CYP11B1 gene of a patient with CAH due to deficiency of steroid 11β-hydroxylase activity, and to study the functional and structural consequences of these mutations. A molecular genetic analysis of the CYP11B1 gene in this patient and her parents identified a known missense mutation g.5194G>C (p.D63H) and a novel 2 bp deletion mutation (g.9525_9526delCT, corresponding to p.L380V…R420X) in the patient. In vitro expression studies in COS7 cells revealed a decreased 11β-hydroxylase activity in the p.D63H mutant to 2.0±0.8% and in the p.L380V…R420X mutant to 0.2±2.2% for the conversion of 11-deoxycortisol to cortisol. Three dimensional homology models for the normal and mutant proteins were built by using the recently published x-ray structure of the human CYP11B2 as a template. Presumably, the g.9525_9526delCT mutation in CYP11B1 resulted in a truncated protein with a misfolded C-terminal domain that could not efficiently bind heme iron, substrate, and adrenodoxin and had lost its biochemical function. In summary, CAH due to steroid 11β-hydroxylase deficiency can be attributed to both the novel deletion mutation (g.9525_9526delCT, corresponding to p.L380V…R420X) and known missense mutation (g.5194G>C corresponding to p.D63H) in CYP11B1.
authors.affiliation: Laboratory of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P R China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Long
authors.forename: Su
authors.initials: S
authors.lastname: Han
authors.forename: Xiangxun
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Haoming
authors.initials: H
authors.lastname: Tian
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002681:China; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D006801:Humans; D008595:Menorrhagia / Q000209:etiology / Q000503:physiopathology; D020125:Mutation, Missense; D010290:Parents; D010375:Pedigree; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012720:Severity of Illness Index; D013252:Steroid 11-beta-Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D040681:Structural Homology, Protein
chemical_list: D011994:Recombinant Proteins; D013252:Steroid 11-beta-Hydroxylase