Original Research ARTICLE
A novel compound heterozygous CYP17A1 variant causes 17α-hydroxylase/17,20-lyase deficiency
- 1First Affiliated Hospital, College of Medicine, Zhejiang University, China
- 2College of life science, Zhejiang Chinese Medical University, China
- 3City of Hope National Medical Center, United States
- 4College of Life Science, Zhejiang University, China
Background: Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive diseases characterized by enzyme deficiencies within steroid hormone anabolism which lead to disorders in cortisol synthesis. The 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is an uncommon form of CAH caused by variants in the CYP17A1 gene.
Aims: We report a novel compound heterozygous CYP17A1 variant and its association with the pathogenesis of 17-OHD.
Methods: The patient was assessed formedical history, clinical manifestations, physical examination, laboratory examination, karyotype analysis and adrenal computed tomography. Mutation screening was conducted using whole exome sequencing (WES) and Sanger sequencing. The wild-type and mutant CYP17A1 cDNA were amplified and cloned into a pcDNA3.1(+) vector. These plasmids were transfected transiently into HEK-293T cells, respectively. Quantitative PCR and Western blotting analysis were performed to measure the expression level of P450c17. An enzymatic activity assay was conducted measuring the content of 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterones (DHEA) in medium using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Results: The proband was characterized by 17-OHD with rhabdomyolysis, hypokalemia and adrenal insufficiency. Novel compound heterozygous variants of the CYP17A1 gene (c.1304T>C/p.Phe435Ser and c.1228delG/p.Asp410Ilefs*9) were identified. The enzymatic activity assay revealed that this variant resulted in a complete deficiency of 17α-hydroxylase and 17,20-lyase activity. This was consistent with the hormonal characteristics of the proband’s blood.
Conclusions: These results suggest that the compound heterozygous variant of c.1304T>C and c.1228delG of the CYP17A1 gene can lead to17-OHD. Our findings thus provide a novel insight into the clinical evaluations and molecular basis of 17-OHD.
Keywords: CYP17A1 gene, 17α-hydroxylase/17,20-lyase deficiency, congenital adrenal hyperplasia, Rhabdomyolysis, Mutation
Received: 30 Oct 2018;
Accepted: 18 Sep 2019.
Copyright: © 2019 Chen, Chen, Jia, Zhu, Sun, Zhou, Zhang, Huang, Liang, Yan and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Prof. Li Liang, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China, firstname.lastname@example.org
Prof. Qingfeng Yan, Zhejiang University, College of Life Science, Hangzhou, China, email@example.com
Dr. Chunlin Wang, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China, firstname.lastname@example.org