Dataset Information

A novel chimeric CYP11B2/CYP11B1 combined with a new p.L340P CYP11B1 mutation in a patient with 11OHD: case report.

ABSTRACT: BACKGROUND11?-Hydroxylase deficiency (11OHD) is a common form of congenital adrenal hyperplasia that has been shown to result from inactivating CYP11B1 mutations, and pathogenic CYP11B2/CYP11B1 chimeras contribute to a minority of cases. Heterozygote cases (chimeras combined with missense mutation) are very rare, and genetic analysis of these cases is difficult.CASE PRESENTATIONWe describe an 11OHD patient presenting with precocious pseudopuberty and hypokalemia hypertension who harbored a chimeric CYP11B2/CYP11B1 with a novel breakage point located at g.9559-9742 of CYP11B2. Interestingly, the other allele exhibited a new mutation, p.L340P, in CYP11B1. Bioinformatics and molecular dynamics simulation indicated that p.L340P decreased the stability and changed the surface configuration of 11?-hydroxylase, indicating a disease-causing mutation. Further pedigree study, PCR and next-generation sequencing indicated that the proband carried both the chimera and p.L340P, and coexistence of the two increased the severity of 11OHD in this family. After treatment with combined medications, blood pressure and clinical parameters improved.CONCLUSIONSOur results suggest that chimera screening and CYP11B1 mutation screening should be simultaneously conducted, and pedigree study is necessary.

SUBMITTER: Duan L

PROVIDER: S-EPMC5921981 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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A novel chimeric CYP11B2/CYP11B1 combined with a new p.L340P CYP11B1 mutation in a patient with 11OHD: case report.

Duan Lian L Shen Rufei R Song Lingyu L Liao Yong Y Zheng Hongting H

BMC endocrine disorders 20180427 1

<h4>Background</h4>11β-Hydroxylase deficiency (11OHD) is a common form of congenital adrenal hyperplasia that has been shown to result from inactivating CYP11B1 mutations, and pathogenic CYP11B2/CYP11B1 chimeras contribute to a minority of cases. Heterozygote cases (chimeras combined with missense mutation) are very rare, and genetic analysis of these cases is difficult.<h4>Case presentation</h4>We describe an 11OHD patient presenting with precocious pseudopuberty and hypokalemia hypertension wh ...[more]

PMID: 29703198

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Project description:BackgroundCongenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency (11β-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11β-OHD and analyze the effects of a splicing mutation.Case presentationA 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty. Hormonal studies suggested 11β-OHD. Mutation analysis was performed by PCR followed by Sanger sequencing of the entire coding regions and their flanking introns of the CYP11B1 gene. Mutation analysis showed that both patients were compound heterozygous for IVS7 + 1G > A, and c.421C > T. Although the identified mutations have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. A minigene assay was used to determine the effects of the splicing mutation. The constructs containing either the wild-type or the splice-site mutant CYP11B1 genomic DNA of exons-introns 6-9 were transfected into COS-7 cells; subsequently, RNA splicing was assessed by reversed transcribed-PCR of CYP11B1 complementary DNA. The minigene assay revealed that the IVS7 + 1G > A mutation resulted in two shorter incorrectly spliced products; one skipping the exon 7 and the other skipping the exons 7-8. The c.421C > T mutation leads to the introduction of a premature stop codon at residue 141 (p.R141X). These mutations are expected to code non-functional proteins.ConclusionCompound heterozygous mutations (IVS7 + 1G > A and p.R141X) in the CYP11B1 gene were found to cause 11β-OHD. The IVS7 + 1G > A mutation causes aberrant splicing of CYP11B1 leading to exon skipping. This finding could facilitate the future novel therapies targeted on splicing modulation to treat human disease.

Project description:BackgroundAldosterone synthase (CYP11B2) deficiency is a rare autosomal recessive disorder, usually presenting with severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood. Neonatal screening for congenital adrenal hyperplasia, another cause of salt wasting, using 17-hydroxyprogesterone measurement would fail to detect aldosterone synthase deficiency, a diagnosis which may be missed until the patient presents with salt-wasting crisis. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation for suspected patients would facilitate clinical management of the patient and assessment of the genetic implication in their offspring.Case presentationWe describe a 33-year old Chinese man who presented in infancy with life-threatening hyponatraemia and failure to thrive, but remained asymptomatic on fludrocortisone since. Chromosomal analysis confirmed a normal male karyotype of 46, XY. Plasma steroid profile showed high plasma renin activity, low aldosterone level, and elevated 18-hydroxycorticosterone, compatible with type 2 aldosterone synthase deficiency. The patient was heterozygous for a novel CYP11B2 mutation: c.977C > A (p.Thr326Lys) in exon 3. He also carried a heterozygous mutation c.523_525delAAG (p.Lys175del) in exon 6, a known pathogenic mutation causing aldosterone synthase deficiency. Sequencing of CYP11B2 in his parents demonstrated that the mother was heterozygous for c.977C > A, and the father was heterozygous for c.523_525delAAG.ConclusionAlthough a rare cause of hyperreninaemic hypoaldosteronism, aldosterone synthase deficiency should be suspected and the diagnosis sought in patients who present with life-threatening salt-wasting in infancy, as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted. To our knowledge, this is the first Chinese patient in which the molecular basis of aldosterone synthase deficiency has been identified.

Dataset Information

A novel chimeric CYP11B2/CYP11B1 combined with a new p.L340P CYP11B1 mutation in a patient with 11OHD: case report.

Publications

A novel chimeric CYP11B2/CYP11B1 combined with a new p.L340P CYP11B1 mutation in a patient with 11OHD: case report.

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