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.
Highlights
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
CAH results in a series of clinical manifestations including insufficient or complete lack of cortisol synthesis, adrenocorticotropic hormone (ACTH) secretion feedback, and increased and stimulated adrenal cortical cell proliferation (Yanase et al, 1991; Turcu and Auchus, 2015)
The concentration of DHEA was 0.72 ± 0.04 nmol/L in the p.Phe435Ser/p.Asp410Ilefs*9 compound heterozygous variant (Figure 3D). These results indicated that the novel c.1304T > C and c.1228delG compound heterozygous variants of CYP17A1 resulted in almost complete deficiencies of 17α-hydroxylase and 17,20-lyase activity, which were consistent with the blood hormonal characteristic of the proband
Summary
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 These genetic defects can hinder the synthesis of glucocorticoids, mineralocorticoids, or sex hormones and lead to the accumulation of upstream products. Different mutations in the CYP17A1 gene result in a series of impaired or reduced functions relating to reduce P450c17 enzyme activity, leading to a range of clinical problems. The 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is an uncommon form of CAH caused by variants in the CYP17A1 gene
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