Journal
FRONTIERS IN GENETICS
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2019.00996
Keywords
CYP17A1 gene; 17 alpha-hydroxylase/17,20-lyase deficiency; congenital adrenal hyperplasia; rhabdomyolysis; variant
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Funding
- National Basic Research Program of China [2014CB943001]
- National Natural Science Foundation of China [11571309, 31771398, 31571299]
- Fundamental-Research Funds for the Central Universities [2019QNA6001]
- Zhejiang Provincial Natural Science Foundation of China [LZ19C060001]
- National Institute of Health [NCI 2R01CA139158]
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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 17 alpha-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 17 alpha-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.
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