A Novel Compound Heterozygous CYP17A1 Variant Causes 17α-Hydroxylase/17, 20-Lyase Deficiency

Hong Chen; Ke Yuan; Bingtao Zhang; Zexiao Jia; Chun Chen; Yilin Zhu; Yaping Sun; Hui Zhou; Wendong Huang; Li Liang; Qingfeng Yan; Chunlin Wang

doi:10.3389/fgene.2019.00996

A Novel Compound Heterozygous CYP17A1 Variant Causes 17α-Hydroxylase/17, 20-Lyase Deficiency

Front Genet. 2019 Oct 22:10:996. doi: 10.3389/fgene.2019.00996. eCollection 2019.

Authors

Hong Chen¹, Ke Yuan¹, Bingtao Zhang², Zexiao Jia², Chun Chen¹, Yilin Zhu¹, Yaping Sun², Hui Zhou², Wendong Huang³, Li Liang¹, Qingfeng Yan^{1

2

4}, Chunlin Wang¹

Affiliations

¹ Department of Pediatrics, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou, China.
² College of Life Science, Zhejiang University, Hangzhou, China.
³ Department of Diabetes Complications and Metabolism, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
⁴ Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, China.

Abstract

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 for medical 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 complementary DNAs (cDNAs) were amplified and cloned into a pcDNA3.1(+) vector. These plasmids were transfected transiently into HEK-293T cells. Quantitative PCR and Western blotting analysis were performed to measure the expression level of P450c17. An enzymatic activity assay was conducted to measure the content of 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone (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 to 17-OHD. Our findings thus provide a novel insight into the clinical evaluations and molecular basis of 17-OHD.

Keywords: 17α-hydroxylase/17,20-lyase deficiency; CYP17A1 gene; congenital adrenal hyperplasia; rhabdomyolysis; variant.