Clinical diagnosis and genetic analysis of 46,XY complete gonadal dysplasia caused by a new mutation of NR5A1 gene / 现代泌尿外科杂志

【Objective】 To investigate the clinical characteristics and molecular genetic mechanism of 46,XY complete gonadal dysplasia (46,XY CGD) caused by a new mutation of NR5A1 gene. 【Methods】 The clinical data of a female patient with 46 XY karyotype were retrospectively analyzed, and the whole exon group and mitochondrial group genes were detected. 【Results】 The clitoris was hypertrophic. The patient had both urethral orifice and vaginal orifice, and there was no common passage between them. Ultrasonography showed an unclear primordial uterus and bilateral ovaries. The gonad biopsy showed poorly developed testicular tissue. Karyotype was 46,XY. The detection of whole exon group and mitochondrial group genes indicated a new heterozygous missense mutation in NR5A1 gene on chromosome 9, and the variation information was c.205C>T:p. Arg69Cys. The mother did not carry the gene mutation. 【Conclusion】 The clinical manifestations of 46,XY CGD are diverse. NR5A1 gene mutation is one of the important causes, which provides a basis for the clinical diagnosis and pathogenesis of the disease.

Epididymis cell atlas in a patient with a sex development disorder and a novel NR5A1 gene mutation / 亚洲男科学杂志(英文版)

This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development (DSD) patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene. Next-generation sequencing found a heterozygous c.124C>G mutation in NR5A1 that resulted in a p.Q42E missense mutation in the conserved DNA-binding domain of NR5A1. The patient demonstrated feminization of external genitalia and Tanner stage 1 breast development. The surgical procedure revealed a morphologically normal epididymis and vas deferens but a dysplastic testis. Microfluidic-based single-cell RNA sequencing (scRNA-seq) analysis found that the fibroblast cells were significantly increased (approximately 46.5%), whereas the number of main epididymal epithelial cells (approximately 9.2%), such as principal cells and basal cells, was dramatically decreased. Bioinformatics analysis of cell-cell communications and gene regulatory networks at the single-cell level inferred that epididymal epithelial cell loss and fibroblast occupation are associated with the epithelial-to-mesenchymal transition (EMT) process. The present study provides a cell atlas of the epididymis of a patient with 46,XY DSD and serves as an important resource for understanding the pathophysiology of DSD.

Advance in mutations of steroidogenic factor-1 and the related clinical phenotype / 中华内分泌代谢杂志

Steroidogenic factor-1 (SF-1, NR5A1) is a transcription factor that plays a key role in the development of gonad and adrenal gland. NR5A1 gene mutation is one of the common causes of disorders of sex development(DSD). Heterozygous mutations of NR5A1 gene accounts for the majority of reported cases with various phenotyre. Early reported cases manifested with varying degrees of 46, XY gonadal dysplasia, whereas NR5A1 mutation was revealed to be related with the phenotypes of azoospermia in men and premature ovarian insufficiency in women recently. Adrenocortical insufficiency is absent in most cases. The heterogeneity of the clinical phenotype is considered resulting from the functional impact of different gene mutations on transcriptional activity, dose effect of downstream target gene(such as SOX9)and the genetic background of oligogenic mutation, etc. The process and regulation of gonadal development might be understood comprehensively by investigating the genotype and related phenotype of NR5A1.

Recent progress of NR5A1 gene mutation / 国际儿科学杂志

NR5A1 gene mutation is one of the common cause of 46 XY dysplasia (46,XY disorder of sex development,46,XY DSD),which is an autosomal dominant disease.It has wide phenotypes:46,XY gonadal dysplasia is the most common one,site-specific mutations can lead to adrenal dysfunction and may affect the height.In recent years,more and more studies have shown that the mutation of NR5A1 gene can lead to 46,XX ovotesticular DSD and 46,XX testicular DSD.The disease is also characterized by hypergonadotropic hypogonadism,so LH and FSH are high,especially the FSH,leading to a decrease in LH/FSH.The treatment of NR5A1 gene mutation is mainly symptomatic.Gender identification needs to take many factors into consideration.Before puberty,children can use GnRHa to inhibit gonad development and avoid premature ovarian failure.In this review,recent progress of NR5A1 is summarized.

New phenotype caused by a NR5A1 heterozygous mutation—— 46, XX disorder of sex development / 中华内分泌代谢杂志

Objective To summarize the clinical manifestations of 46, XX ovotesticular disorder of sex development (DSD) caused by a NR5A1 heterozygous mutation. Methods The first case of 46,XX ovotesticular DSD was caused by a NR5A1 heterozygous mutation in China and was reported with a review of 11 similar cases in the literatures since July 2016. Results A 5. 6-year-old child raised as female was born with ambiguous genitalia. The left gonad was palpable in the inguinal region while the right one was located in abdomen. Gonadal histology showed both ovotestis. Vaginoscopy revealed a short, blind-ending vagina. No uterine was detected by laparoscopy. Repeated karyotype results were 46, XX with SRY gene negative. A heterozygous de novo mutation ( p. Arg92Trp) in the accessory DNA-binding region of NR5A1 gene was found in that child. Conclusions We reported for the first time in China a new phenotype caused by a NR5A1 heterozygous mutation-46,XX ovotesticular DSD. According to the review of literatures, such mutation seemed with incomplete penetrance. It could cause both 46, XX DSD and 46, XY DSD with varied manifestations. The possible underlying mechanism might relate to the impairment of the binding between the mutant protein and target DNA which might lead to a decreased inhibition of the male developmental pathway through downregulation of female antitestis genes.

New phenotype caused by a NR5A1 heterozygous mutation—— 46, XX disorder of sex development / 中华内分泌代谢杂志

Objective To summarize the clinical manifestations of 46, XX ovotesticular disorder of sex development (DSD) caused by a NR5A1 heterozygous mutation. Methods The first case of 46,XX ovotesticular DSD was caused by a NR5A1 heterozygous mutation in China and was reported with a review of 11 similar cases in the literatures since July 2016. Results A 5. 6-year-old child raised as female was born with ambiguous genitalia. The left gonad was palpable in the inguinal region while the right one was located in abdomen. Gonadal histology showed both ovotestis. Vaginoscopy revealed a short, blind-ending vagina. No uterine was detected by laparoscopy. Repeated karyotype results were 46, XX with SRY gene negative. A heterozygous de novo mutation ( p. Arg92Trp) in the accessory DNA-binding region of NR5A1 gene was found in that child. Conclusions We reported for the first time in China a new phenotype caused by a NR5A1 heterozygous mutation-46,XX ovotesticular DSD. According to the review of literatures, such mutation seemed with incomplete penetrance. It could cause both 46, XX DSD and 46, XY DSD with varied manifestations. The possible underlying mechanism might relate to the impairment of the binding between the mutant protein and target DNA which might lead to a decreased inhibition of the male developmental pathway through downregulation of female antitestis genes.

NR5A1 gene mutation in child with 46, XY disorders of sex development：a case report and literature review / 临床儿科杂志

Objective To explore the clinical features and molecular diagnosis of 46, XY disorder of sex development (46, XY DSD).Methods The clinic data of one child with 46, XY DSD raised as female were retrospectively analyzed, and related literatures were reviewed.Results The 11.5-year-old child raised as female visited clinic due to, “accidently found clitoral hypertrophy for half month”. Preliminary series of laboratory examinations supported the diagnosis of 46, XY DSD, high gonadal hormone dysplasia. DNA sequencing of the whole genome exon group showed a heterozygous mutation of c.937C>T, p.Arg313Cys inNR5A1 gene. No abnormality was detected in her father, while her mother was a heterozygous mutation carrier. Conclusions 46, XY DSD can be diagnosed by the whole genome exon gene sequencing.

Mutation analysis of NR5A1 gene in children with idiopathic hypogonadotropic hypogonadism / 中华内分泌代谢杂志

Objective To study the NR5A1 gene mutation in patients with idiopathic hypogonadotropic hypogonadism(IHH), and to find the new mutation point.Methods Sixty-one IHH patients and 100 normal control subjects were collected and genomic DNA was extracted from blood samples.These patients were with normal karyotype and no abnormality was discovered in magnetic resonance imaging (MRI) scan of the pituitary.Other endocrine diseases were also excluded.The 2-7 exons and splice-sites of NR5A1 gene were amplified with polymerase chain reaction.DNA of the coding sequence and splice-sites of NR5A 1 were sequenced by double deoxidizing terminal end sequencing method in 61 IHH and 100 normal control subjects.The results of sequencing were compared with their corresponding sequence data.61 IHH kindreds were investigated and the clinical data of these patients were collected.Finally, the phenotype and genotype positive cases were analyzed.Results Six patients carried NR5A1 gene mutational sites in 61 cases of IHH.Analysis of sequencing results from 100 age and ethnicity matched control subjects did not show any of these novel changes.Conclusions One mutation in NR5A1 gene may affect protein structure and function, which should be considered in male IHH patients with normal karyotype and without insufficiency of adrenal function.

Multifunctional role of steroidogenic factor 1 and disorders of sex development / Papel multifuncional do fator esteroidogênico 1 e as doenças do desenvolvimento sexual

Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1.

Os distúrbios do desenvolvimento sexual (DDS) envolvem várias condições que resultam de anormalidades que podem acontecer tanto na determinação como durante a diferenciação gonadal. Algumas dessas doenças podem se manifestar ao nascimento principalmente por genitália ambígua, outras são diagnosticadas apenas na puberdade por atraso no aparecimento de características sexuais secundárias. A determinação e a diferenciação do sexo em seres humanos são processos que envolvem interações entre vários genes nas vias testicular, tais como NR5A1, NR0B1, WT1, SOX9, entre outros, e ovariana, tais como WNT4, DAX1, FOXL2 e RSPO1. Uma das principais proteínas na diferenciação gonadal de mamíferos é o fator esteroidogênico e receptor nuclear 1 (SF1). Esta revisão cobrirá alguns dos dados mais recentes sobre os papéis funcionais de SF1 e as últimas descobertas relacionadas a mutações em seu gene, NR5A1.