Lessons from 17β-HSD3 deficiency: Clinical spectrum and complex molecular basis in Chinese patients. Issue 225 (January 2023)

• Record Type: Journal Article
• Authors: Zhu, Hui; Yao, Haijun; Liu, Xuemeng; Xu, Yue; Liu, Yang; Luo, Qingqiong; Chen, Yan; Shi, Yuanping; Chen, Fuxiang; Zhao, Shuangxia; Song, Huaidong; Han, Bing; Qiao, Jie
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 225(2022)
• Publication Date: 2023-01
• Subjects: 17β-HSD3 17β-hydroxysteroid dehydrogenase type 3 -- DSD disorder/differences of sex development -- T testosterone -- AD Δ4- androstenedione -- T/AD testosterone/androstenedione ratio -- hCG human chorionic gonadotropin -- 5α-RD2 5α-reductase 2 deficiency -- NGS next-generation sequencing -- SNPs single-nucleotide polymorphisms -- DHEA dehydroepiandrosterone -- LC-MS/MS liquid chromatography-tandem mass spectrometry -- LH luteinizing hormone -- FSH follicle-stimulating hormone -- VUS variants of uncertain clinical significance -- ACMG American College of Medical Genetics and Genomics -- WT wild-type -- HEK human embryonic kidney -- DMEM Dulbecco's modified Eagle's medium -- FBS fetal bovine serum -- MAF minimum allele frequency -- RT-PCR reverse transcription PCR -- NF1 neurofibromatosis type 1 -- ATM ataxia telangiectasia mutated; 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency -- HSD17B3 mutation -- Disorder/differences of sex development (DSD) -- Functional assay; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2022.106191
• Languages: English
• ISSNs: 0960-0760

Abstract

Abstract: 17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency is rarely reported in Chinese patients with 46, XY disorders of sexual development (DSD). Seven subjects with 17β-HSD3 deficiency were identified from 206 Chinese 46, XY DSD patients using targeted next-generation sequencing (NGS). Serum AD and T levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In silico and functional studies were performed to evaluate the enzymatic activity impairment of HSD17B3 variants. A minigene assay was performed in an exonic splicing variant. Our results showed that four novel and five reported HSD17B3 variants were identified in 7 unrelated patients. The patients showed cryptic presentation during childhood and classical virilization after puberty with T/AD ratio< 0.4. A heterozygous large deletion from the 5'UTR to exon 1 was identified in a patient with a monoallelic variant of p.N130S. Although predicted to be 'likely pathogenic', only p. S232P and p. S160F drastically reduced the enzymatic activity of 17β-HSD3. A previously reported 'missense' variant c 0.277 G>A (p. E93K) was revealed to have no impact on enzyme activity but resulted in aberrant splicing of exon 3 and was reclassified as an exonic splicing variant. In our study, one nonsense, one exonic splicing, one deletion, one large deletion and five missense variants were detected in patients with 17β-HSD3 deficiency, expanding the clinical and molecular profile of this disorder. In silico analysis should be cautiously interpreted when the heredity pattern and functional study are inconsistent. Highlights: 17β-HSD3 deficiency has been rarely reported in Chinese patients. Postpubertal serum T/AD< 0.4 measured by LC-MS/MS support the diagnosis of 17β-HSD3 deficiency. Functional study rather than in silico analysis should be performed to illustrate the pathogenicity of variants.