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 |
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22.10.2019
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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. |
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AbstractList | 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. 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. |
Author | Zhang, Bingtao Chen, Chun Huang, Wendong Wang, Chunlin Liang, Li Chen, Hong Zhu, Yilin Zhou, Hui Yuan, Ke Sun, Yaping Jia, Zexiao Yan, Qingfeng |
AuthorAffiliation | 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 |
AuthorAffiliation_xml | – name: 1 Department of Pediatrics, The First Affiliated Hospital, College of Medicine Zhejiang University , Hangzhou , China – name: 4 Key Laboratory for Cell and Gene Engineering of Zhejiang Province , Hangzhou , China – name: 3 Department of Diabetes Complications and Metabolism, The Beckman Research Institute, City of Hope National Medical Center , Duarte, CA , United States – name: 2 College of Life Science, Zhejiang University , Hangzhou , China |
Author_xml | – sequence: 1 givenname: Hong surname: Chen fullname: Chen, Hong – sequence: 2 givenname: Ke surname: Yuan fullname: Yuan, Ke – sequence: 3 givenname: Bingtao surname: Zhang fullname: Zhang, Bingtao – sequence: 4 givenname: Zexiao surname: Jia fullname: Jia, Zexiao – sequence: 5 givenname: Chun surname: Chen fullname: Chen, Chun – sequence: 6 givenname: Yilin surname: Zhu fullname: Zhu, Yilin – sequence: 7 givenname: Yaping surname: Sun fullname: Sun, Yaping – sequence: 8 givenname: Hui surname: Zhou fullname: Zhou, Hui – sequence: 9 givenname: Wendong surname: Huang fullname: Huang, Wendong – sequence: 10 givenname: Li surname: Liang fullname: Liang, Li – sequence: 11 givenname: Qingfeng surname: Yan fullname: Yan, Qingfeng – sequence: 12 givenname: Chunlin surname: Wang fullname: Wang, Chunlin |
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Snippet | Background:
Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive diseases characterized by enzyme deficiencies, within steroid... Background: Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive diseases characterized by enzyme deficiencies, within steroid... |
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SubjectTerms | 17α-hydroxylase/17,20-lyase deficiency congenital adrenal hyperplasia CYP17A1 gene Genetics rhabdomyolysis variant |
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Title | A Novel Compound Heterozygous CYP17A1 Variant Causes 17α-Hydroxylase/17, 20-Lyase Deficiency |
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