Novel<i><scp>NR</scp>5A1</i>mutations found in Chinese patients with 46,<scp>XY</scp>disorders of sex development

Yu, Bingqing; Liu, Zhaoxiang; Gao, Yinjie; Mao, Jiangfeng; Wang, Xi; Hao, Ming; Ma, Wanlu; Huang, Qibin; Zhang, Rui; Wu, Xueyan

doi:10.1111/cen.13831

Cited by 9 publications

(9 citation statements)

References 45 publications

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“…Patients and methods have been described in detail previously [ 24 ]. Briefly, 60 patients with 46, XY DSD were admitted to the Endocrinology Department of Peking Union Medical College Hospital, Beijing between January 2010 and October 2015.…”

Section: Methodsmentioning

confidence: 99%

“…Targeted next-generation sequencing and Sanger sequencing were used to identify and validate the gene mutation, respectively. The gene panel (NimblegenSeqCap EZ system, Roche, Basel, Switzerland) was designed to capture all exons and 50-bp flanking intron sequences of 83 DSD-related genes [ 24 ]. A variant was recognized as an underlying disease-causing variant when it was not found in dbSNP, ExAC, GnomAD, and Ensemble database and in 500 Chinese controls, or alternatively, when the allele frequency was found to be less than 0.001 in the database.…”

Section: Methodsmentioning

confidence: 99%

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Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing

Yu¹,

Gao²,

Mao³

et al. 2021

Orphanet J Rare Dis

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Objective To identify the pathogenic mechanism of the c.244G>T mutation in NR5A1 gene found in a Chinese patient with 46, XY disorders of sex development (DSD). Subjects and methods: Genomic DNA was extracted from a Chinese 46, XY DSD patient. Targeted next-generation and Sanger sequencing were performed to investigate and validate the gene mutation causing 46, XY DSD, respectively. In silico tools were used to predict the pathogenicity of the variant. Dual luciferase reporter gene assay and minigene splicing reporter assay were used to identify the pathogenicity of the variant. Results A novel heterozygous variant, c.244G>T (p.Ala82Ser), in NR5A1 gene was detected in the 46, XY DSD patient. Four of five silico tools predicting pathogenicity of missense variants indicated that the variant was pathogenic. However, in vitro functional study showed that p.Ala82Ser did not affect the transcriptional activity of NR5A1. In silico tools predicting the potential splicing loci revealed that c.244G>T led to aberrant splicing of NR5A1 RNA. Minigene splicing reporter assay confirmed that c.244G>T resulted in the deletion of exon2 or deletion of 19 nucleotides in 3′ end of exon2. Conclusions Mutation of c.244G>T in NR5A1 results in 46, XY DSD by inducing abnormal splicing of NR5A1 RNA instead of amino acid substitution of NR5A1.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing

Yu¹,

Gao²,

Mao³

et al. 2021

Orphanet J Rare Dis

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“…Bioinformatic analysis including quality control, reads alignment, and variants calling (including single-nucleotide variations [SNVs] and small indels) was performed following the pipelines previously described. 13 …”

Section: Methodsmentioning

confidence: 99%

Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients

et al. 2020

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Partial congenital hypogonadotropic hypogonadism (PCHH) is caused by an insufficiency in, but not a complete lack of, gonadotropin secretion. This leads to reduced testosterone production, mild testicular enlargement, and partial pubertal development. No studies have shown the productivity of spermatogenesis in patients with PCHH. We compared the outcomes of gonadotropin-induced spermatogenesis between patients with PCHH and those with complete congenital hypogonadotropic hypogonadism (CCHH). This retrospective study included 587 patients with CHH who were treated in Peking Union Medical College Hospital (Beijing, China) from January 2008 to September 2016. A total of 465 cases were excluded from data analysis for testosterone or gonadotropin-releasing hormone treatment, cryptorchidism, poor compliance, or incomplete medical data. We defined male patients with PCHH as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. A total of 122 compliant, noncryptorchid patients with PCHH or CCHH received combined human chorionic gonadotropin and human menopausal gonadotropin and were monitored for 24 months. Testicular size, serum luteinizing hormone levels, follicle-stimulating hormone levels, serum total testosterone levels, and sperm count were recorded at each visit. After gonadotropin therapy, patients with PCHH had a higher spermatogenesis rate (92.3%) than did patients with CCHH (74.7%). During 24-month combined gonadotropin treatment, the PCHH group took significantly less time to begin producing sperm compared with the CCHH group (median time: 11.7 vs 17.8 months, P < 0.05). In conclusion, after combined gonadotropin treatment, patients with PCHH have a higher spermatogenesis success rate and sperm concentrations and require shorter treatment periods for sperm production.

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“…The novel c.64G > T (p.G22C) mutation reported in the present study is a missense mutation, which reportedly accounts for 58% of NR5A1 mutations [6]. The p.G22C is located in the DBD, which is one of three domains in NR5A1, and previous studies have reported this as the location for multiple mutations in patients with 46, XY DSD [6, 20,23,24]. A previous study identi ed a G35E substitution in the DBD region in a patient with 46, XY DSD presenting adrenal insu ciency along with moderately severe gonadal dysplasia, indicating that this variation results in serious adverse effects on NR5A1 function [20].…”

Section: Discussionmentioning

confidence: 58%

A novel c.64G>T (p.G22C) NR5A1 mutation in a Chinese adolescent with 46, XY disorders of sex development: a case report

Zhang

Wang

Tong

et al. 2022

Preprint

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Background Adolescents with 46, XY disorders of sex development (DSD) face additional medical and psychological challenges. To optimize management and minimize hazards, correct and early clinical and molecular diagnosis is necessary. Case presentation: We report a 13-year-old Chinese adolescent with absent Müllerian derivatives and suspected testis in the inguinal area. History, examinations, and investigations were available for clinical diagnosis, and subsequent genetic sequencing was employed for molecular diagnosis. We identified a novel variation in nuclear receptor subfamily 5 group A member 1 (NR5A1) [c.64G > T (p.G22C)] in the patient. In vitro functional analyses of the novel variant suggested no impairment to NR5A1 mRNA or protein expression relative to wild-type, and immunofluorescence confirmed similar localization of the NR5A1 mutant to the cell nucleus. However, we observed decreased DNA-binding affinity by the NR5A1 variant, while dual-luciferase reporter assays showed that the mutant effectively downregulated the transactivation capacity of anti-Müllerian hormone. We described a novel NR5A1 variant and demonstrated its adverse effects on the functional integrity of the NR5A1 protein resulting in serious impairment of its modulation of gonadal development. Conclusions This study provides deeper insights into the NR5A1 mutational spectrum.

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NovelNR5A1mutations found in Chinese patients with 46,XYdisorders of sex development

Abstract: Four novel mutations in the NR5A1 gene were identified in our cohort with 46, XY DSD, expanding the spectrum of NR5A1 gene mutations. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects.

Cited by 9 publications

References 45 publications

Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing

Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing

Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients

A novel c.64G>T (p.G22C) NR5A1 mutation in a Chinese adolescent with 46, XY disorders of sex development: a case report

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NovelNR5A1mutations found in Chinese patients with 46,XYdisorders of sex development

Abstract: Four novel mutations in the NR5A1 gene were identified in our cohort with 46, XY DSD, expanding the spectrum of NR5A1 gene mutations. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects.

Cited by 9 publications

References 45 publications

Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing

Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing

Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients

A novel c.64G&gt;T (p.G22C) NR5A1 mutation in a Chinese adolescent with 46, XY disorders of sex development: a case report

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A novel c.64G>T (p.G22C) NR5A1 mutation in a Chinese adolescent with 46, XY disorders of sex development: a case report