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; 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/ddw390

Cited by 38 publications

(82 citation statements)

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“…Besides our cases, another sibling group with 46,XX DSD due to the R92W variant has been reported to date [Bashamboo et al, 2016]. The siblings of that study showed a similar gonadal phenotype, and the same rearing sex was selected.…”

Section: Discussionmentioning

confidence: 87%

“…An in vitro assay demonstrated that the R92W variant antagonizes the function of key molecules in the female pathway, such as β-catenin and NR0B1 (DAX1) [Bashamboo et al, 2016;Igarashi et al, 2017], resulting in 46,XX DSD. To date, 12 cases of 46,XX DSD in 10 families have been reported, including the present study, and in 7 of these cases, the decision was made to rear the child as a male.…”

Section: Discussionmentioning

confidence: 99%

“…Six 46,XY cases with a R92W mutation have been reported to date [Bashamboo et al, 2016;Baetens et al, 2017]. Five of these individuals were carriers with no phenotypic consequence.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a heterozygous missense mutation in NR5A1 , p.R92W (c.274C>T), has been identified as a cause of 46,XX testicular/ovo-testicular DSD [Bashamboo et al, 2016;Baetens et al, 2017;Igarashi et al, 2017]. These findings indicated that specific NR5A1 mutations can switch the developmental processes of immature 46,XX gonads toward testicular formation [Igarashi et al, 2017].…”

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confidence: 99%

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Phenotypic Variation in 46,XX Disorders of Sex Development due to the NR5A1 p.R92W Variant: A Sibling Case Report and Literature Review

Takasawa¹,

Igarashi²,

Ono³

et al. 2017

Sex Dev

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Recently, a heterozygous missense mutation in NR5A1, p.R92W, was identified as a cause of 46,XX testicular/ovo-testicular disorders of sexual development (DSD). We report a sibling pair with 46,XX DSD due to an NR5A1 mutation with distinct phenotypes, including external and internal genitalia and gonads, for whom different rearing sexes were selected. Thus, the phenotypes of p.R92W vary, even within a family. The father of the patients showed oligozoospermia with the p.R92W mutation, suggesting that in 46,XY individuals, the mutation would cause various gonadal phenotypes. We review and discuss the general role of the R92W mutation in sexual development.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

“…Six 46,XY cases with a R92W mutation have been reported to date [Bashamboo et al, 2016;Baetens et al, 2017]. Five of these individuals were carriers with no phenotypic consequence.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Phenotypic Variation in 46,XX Disorders of Sex Development due to the NR5A1 p.R92W Variant: A Sibling Case Report and Literature Review

Takasawa¹,

Igarashi²,

Ono³

et al. 2017

Sex Dev

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“…DNA-binding is thought to be stabilized by an 'A' box region immediately adjacent to the DNA-binding domain. Loss-of-function changes in human NR5A1 are associated with a wide spectrum of conditions including gonadal (testicular) dysgenesis, hypospadias, and spermatogenic failure in 46,XY men, as well as primary ovarian insufficiency in 46,XX women (38-42) Three studies have been published recently reporting a specific recurrent point mutation in NR5A1 (p.R92W) is associated with OTDSD/TDSD development in 46,XX individuals in multiple families of different ancestry (35)(36)(37). The clinical details of these cases and mode of inheritance are listed in Table 3.…”

Section: Testis Development Associated With An Nr5a1 Missense Mutationmentioning

confidence: 99%

Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development

et al. 2017

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Human sex determination (SD) involves complex mutually antagonistic genetic interactions of testis‐ and ovary‐determining pathways. For many years, both male and female SD were considered to be regulated by a linear cascade of pro‐male and pro‐female genes, respectively; however, it has become clear that male and female development is achieved through the repression of the alternative state. A gene determining the formation of a testis may function by repressing the female state and vice versa. Uniquely in development, SD is achieved by suppression of the alternate fate and maintained in adulthood by a mutually antagonistic double‐repressive pathway. Here, we review genetic data generated through large‐scale sequencing approaches that are changing our view of how this system works, including the recently described recurrent NR5A1 p.R92W mutation associated with testis development in 46,XX children. We also review some of the unique challenges in the field to establish that mutations, such as this are pathogenic. The impending surge of new genetic data on human SD from sequencing projects will create opportunities for the development of mechanistic models that will clarify how the system operates and importantly provide data to understand how selection and developmental processes interact to direct the evolution of SD across species.

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Functional characterization of fiveNR5A1gene mutations found in patients with 46,XY disorders of sex development

et al. 2017

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Steroidogenic factor-1 (SF1), encoded by the NR5A1 gene, is a key regulator of steroidogenesis and reproductive development. NR5A1 mutations described in 46,XY patients with disorders of sex development (DSD) can be associated with a range of conditions of phenotypes; however, the genotype-phenotype correlation remains elusive in many cases. In the present study, we describe the impact of five NR5A1 variants (three novel: p.Arg39Cys, p.Ser32Asn, and p.Lys396Argfs*34; and two previously described: p.Cys65Tyr and p.Cys247*) on protein function, identified in seven patients with 46,XY DSD. In vitro functional analyses demonstrate that NR5A1 mutations impair protein functions and result in the DSD phenotype observed in our patients. Missense mutations in the DNA binding domain and the frameshift mutation p.Lys396Argfs*34 lead to both, markedly affected transactivation assays, and loss of DNA binding, whereas the mutation p.Cys247* retained partial transactivation capacity and the ability to bind a consensus SF1 responsive element. SF1 acts in a dose-dependent manner and regulates a cascade of genes involved in the sex determination and steroidogenesis, but in most cases reported so far, still lead to a sufficient adrenal steroidogenesis and function, just like in our cases, in which heterozygous mutations are associated to 46,XY DSD with intact adrenal steroid biosynthesis.

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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 38 publications

References 0 publications

Phenotypic Variation in 46,XX Disorders of Sex Development due to the <b><i>NR5A1 </i></b>p.R92W Variant: A Sibling Case Report and Literature Review

Phenotypic Variation in 46,XX Disorders of Sex Development due to the <b><i>NR5A1 </i></b>p.R92W Variant: A Sibling Case Report and Literature Review

Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development

Functional characterization of fiveNR5A1gene mutations found in patients with 46,XY disorders of sex development

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