A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development

Bashamboo, Anu; Donohoue, Patricia A.; Vilain, Éric; Rojo, Sandra; Calvel, Pierre; Seneviratne, Sumudu Nimali; Buonocore, Federica; Barseghyan, Hayk; Bingham, Nathan C.; Rosenfeld, Jill A.; Mulukutla, Surya N.; Jain, Mahim; Burrage, Lindsay C.; Dhar, Shweta U.; Balasubramanyam, Ashok; Lee, Brendan; Dumargne, Marie-Charlotte; Eozénou, Caroline; Suntharalingham, Jenifer P.; Silva, Ksh de; Lin, Lin; Bignon‐Topalovic, Joelle; Poulat, Françis; Lagos, Carlos F.; McElreavey, Ken; Achermann, John C.

doi:10.1093/hmg/ddw186

Cited by 107 publications

(113 citation statements)

References 29 publications

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“…In the XY gonad the activation of SRY expression, possibly initiated by CBX2/WT1/GATA4/FOG2/ NR5A1, leads to the upregulation of Sox9 expression via a synergy with Nr5a1 at a Sox9 enhancer such as Tesco [Sekido and LovellBadge, 2008]. In the XX gonad the supporting cell precursors accumulate β-catenin in response to RSPO1/WNT4 signaling, which either directly or indirectly represses SOX9 expression, perhaps at least in human, by interacting with NR5A1 [Bashamboo et al, 2016]. Once Sox9 levels reach a critical threshold, several positive regulatory loops are initiated, including autoregulation of its own expression and formation of feed-forward loops via FGF9 or PGD2 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…This view was supported by our screen of further 40 cases of 46,XX DSD that did not reveal any other NR5A1 mutations. In 2015, we were contacted by different groups who had also identified the same NR5A1 p.Arg92Trp mutation in association with 46,XX testicular DSD [Bashamboo et al, 2016]. Two families had a single affected child who carried a de novo NR5A1 p.Arg92Trp mutation, and this formally excluded a founder mutation.…”

Section: Nr5a1 Parg92trp and 46xx Dsdmentioning

confidence: 99%

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Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Bashamboo

2016

Sex Dev

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In this review we will consider the gene mutations responsible for the non-syndromic forms of disorders of sex development (DSD) and how recent genetic findings are providing insights into the mechanism of sex determination. High-throughput sequencing technologies are having a major impact on our understanding of the genetic basis of rare human disorders, including DSD. The study of human DSD is progressively revealing subtle differences in the genetics of the sex-determining system between the mouse and the human. This plasticity of the sex-determining pathway is apparent in (a) the difference in phenotypes in human and mouse associated with the same gene, (b) the different gene regulatory mechanisms between human and mouse, and finally (c) the different and unexpected reproductive phenotypes seen in association with mutations in well-studied sex-determining genes.

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Section: Discussionmentioning

confidence: 99%

Section: Nr5a1 Parg92trp and 46xx Dsdmentioning

confidence: 99%

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Bashamboo

2016

Sex Dev

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“…The spectrum of disorders associated with NR5A1 variants in 46,XX individuals was further expanded by the demonstration of the specific recurrent heterozygous p.Arg92Trp NR5A1 variant, in association with variable degrees of testis development in 46,XX patients from unrelated families (Baetens et al, 2016; Bashamboo et al, 2016; Igarashi et al, 2017). The p.Arg92Trp NR5A1 mutation was described in ten SRY negative 46,XX DSD patients, six with testicular DSD and four with ovotesticular DSD.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro assays demonstrated that the p.Arg92Trp mutant lost its binding capacity to a consensus NR5A1 response element and reduced activation of some minimal promoters ( Amh, Cyp11a1 ) (Bashamboo et al, 2016). This mutated protein was also less sensitive to NR0B1‐induced suppression on the SOX9 TESCO element, leading to testis formation (Igarashi et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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“…Phenotypes ranged from ambiguous genitalia, to penoscrotal hypospadias, to micropenis noted at birth, to small testes and low testosterone noted in adolescence. Of note, one proband had a sibling with labial fusion, clitoral enlargement, and dysgenetic testes in the inguinal region who was found to have a 46,XY karyotype and the same NR5A1 mutation [23]*.…”

Section: A Role For Nr5a1 In Ovarian Fate Specificationmentioning

confidence: 99%

Recent findings on the genetics of disorders of sex development

Kremen

Chan²,

Swartz³

2017

Current Opinion in Urology

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Purpose of review Disorders of sex development (DSD) are a diverse group of conditions affecting gonadal development, sexual differentiation or chromosomal sex. In this review, we will discuss recent literature on the genetic causes of DSD, with a focus on novel genetic sequencing technologies, new phenotypes associated with known DSD genes, and increasing recognition of the role of genetic regulatory elements in DSD. Methods We performed a comprehensive search of PubMed through August 2016 to identify important peer-reviewed publications from 2015–2016 on the topic of DSD genetics. Summary of Recent Findings Whole-exome sequencing was used to successfully identify genetic causes of DSD in 35% of a cohort of 46,XY subjects who had not previously received a genetic diagnosis. A novel mutation in NR5A1 has been identified as a cause of 46,XX testicular and ovotesticular DSD, demonstrating a previously unappreciated role of NR5A1 in preventing testicular differentiation in 46,XX individuals. Genetic regulatory elements of SOX9 have been identified as causes of 46,XX and 46,XY DSD.

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A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development

Cited by 107 publications

References 29 publications

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Recent findings on the genetics of disorders of sex development

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