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

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.

Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1–6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience

“…This leads to complete female external genitalia in both sexes when there is complete enzyme deficiency. Therefore, as in our patients and most other case series, the diagnosis of 17OHD before puberty is very rare unless there is a known case in the family [Wang et al, 2012;Chen et al, 2019;Sun et al, 2021;Beştaş et al, 2022]. Clinical findings related to excessive mineralocorticoid effects, such as HT and hypokalemic alkalosis, are important clues for early diagnosis of 17OHD.…”

Hiperplasia adrenal congénita asociada a mutación no descrita en el gen CYP17A1

“…La mutación del gen CYP17A1 debe considerarse al evaluar individuos jóvenes con hipogonadismo, hipertensión con o sin hipokalemia, dado que causa deficiencia de glucocorticoides y andrógenos, pero exceso de mineralocorticoides (9). Más de 100 mutaciones en el gen CYP17A1 se han descrito, las cuales incluyen mutaciones de cambio de sentido, deleciones, inserciones y variantes en los sitios de splicing (10)(11)(12)(13)(14)(15). Reportamos por primera vez en el mundo la mutación de cambio de sentido erróneo, c.1250T>C; p.Phe417Ser, en el gen CYP17A1, relacionada con la HAC.…”

MAP3K1 Variant Causes Hyperactivation of Wnt4/β-Catenin/FOXL2 Signaling Contributing to 46,XY Disorders/Differences of Sex Development

“…Briefly, genomic DNA was obtained from both the proband and her parents via peripheral blood leukocytes using standard procedures. We then performed whole-exon sequencing (WES) as previously described ( Chen et al, 2019 ). The Sanger sequencing variant detected in the MAP3K1 gene was described according to the NCBI entry NG_031884.1 (NM_005921.2).…”