title: Chimeric CYP11B2/CYP11B1 causing 11β-hydroxylase deficiency in Chinese patients with congenital adrenal hyperplasia.
abstract: CYP11B1 and CYP11B2 are highly homologous genes that can form chimera following unequal crossing-over during meiosis. A chimeric CYP11B1/CYP11B2 gene causes glucocorticoid-remediable aldosteronism (GRA), while the rare CYP11B2/CYP11B1 chimeric gene leads to 11β-hydroxylase deficiency (11-OHD). The aim of the study was to find the underlying genetic causes of three distinct Chinese pedigrees with 11-OHD. The family history, clinical data, laboratory findings and alterations in the CYP11B1 gene sequence were analyzed in all patients. We found that patient 1 and patient 2 harbored novel homozygotic chimeric CYP11B2/CYP11B1 genes consisting of the promoter, exons 1-6 of CYP11B2, and exons 7-9 of CYP11B1. Patient 3 had compound heterozygotic mutation with one allele containing the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1, and the other allele comprising novel, previously undescribed p.W56X (c.168G>A) mutation in exon 1 of CYP11B1. The breakpoints to form Chimeric CYP11B2/CYP11B1 were not the same for the three patients. Rare chimeric CYP11B2/CYP11B1 gene mutations are the underlying cause of disease in three patients with 11-OHD. We hypothesize that the lack expression of CYP11B1 under the control of the CYP11B2 promoter in zona fasciculata may contribute to a cortisol defect as well as the resultant 11-OHD.
authors.affiliation: Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Endocrinology, Ministry of Health, Beijing, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Endocrinology, Ministry of Health, Beijing, China.
authors.forename: Weibo
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Endocrinology, Ministry of Health, Beijing, China.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Endocrinology, Ministry of Health, Beijing, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Endocrinology, Ministry of Health, Beijing, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Endocrinology, Ministry of Health, Beijing, China. Electronic address: nm_pumch@aliyun.com.
authors.forename: Min
authors.initials: M
authors.lastname: Nie
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D003434:Crossing Over, Genetic; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase
keywords: 11β-Hydroxylase deficiency; Chimeric CYP11B2/CYP11B1; Congenital adrenal hyperplasia; Mutation