A Novel Compound Heterozygous CYP17A1 Variant Causes 17α-Hydroxylase/17, 20-Lyase Deficiency
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 c...
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Published in | Frontiers in genetics Vol. 10; p. 996 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
22.10.2019
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Muhammad Umair, Quaid-i-Azam University, Pakistan; Wenbin Zou, Changhai Hospital, China; Jan Idkowiak, University of Birmingham, United Kingdom This article was submitted to Genetic Disorders, a section of the journal Frontiers in Genetics Edited by: Andrew Landstrom, Duke University, United States |
ISSN: | 1664-8021 1664-8021 |
DOI: | 10.3389/fgene.2019.00996 |