Ten Novel Mutations in the NR5A1 Gene Cause Disordered Sex Development in 46,XY and Ovarian Insufficiency in 46,XX Individuals

Camats, Núria; Pandey, Amit V.; Fernández‐Cancio, Mónica; Andaluz, Pilar; Janner, Marco; Torán, Núria; Moreno, Francisca; Bereket, Abdullah; Akçay, Teoman; García-García, Emilio; M, Muñoz Torres; Gracía, Ricardo; Nistal, Manuel; Castaño, Luís; Mullis, Primus Ε.; Carrascosa, Antonio; Audí, Laura; Flück, Christa E.

doi:10.1210/jc.2011-3169

Cited by 116 publications

(177 citation statements)

References 42 publications

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“…First, interallelic association with the known p.Gly146Ala polymorphism (rs1110061) may further reduce NR5A1 activity and contribute to more severe phenotypes (WuQiang et al, 2003; Hasegawa et al, 2004; Wada et al, 2006; Reuter et al, 2007; Köhler et al, 2008; Lourenço et al, 2009; Bashamboo et al, 2010a; Paris et al, 2011; Camats et al, 2012). However, two patients in our cohort also bore the p.Gly146Ala variant besides the pathogenic NR5A1 variants, p.Trp302Cys and p.Tyr404*, and their phenotype was not strikingly distinct or more severe.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, it was shown that NR5A1 mutations are also a genetic cause of POI, with phenotypes ranging from primary to secondary amenorrhea, associated with infertility, hypoestrogenism, and elevated gonadotropin levels (Lourenço et al, 2009; Camats et al, 2012) Sisters and mothers of 46,XY DSD patients carrying heterozygous NR5A1 mutations may also develop premature ovarian failure (Lourenço et al, 2009; Camats et al, 2012; Fabbri et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

“…Several genes required for ovarian steroidogenesis, and follicle growth and maturation are regulated by NR5A1 , explaining why mutant NR5A1 may lead to progressive loss of ovarian function and female reproductive capacity (Lourenço et al, 2009; Camats et al, 2012; Fabbri et al, 2016). Women bearing NR5A1 defects should receive appropriate counseling and fertility guidance, enabling potential oocyte cryopreservation, due to the risk of developing ovarian insufficiency later in life.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

View full text Add to dashboard Cite

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“…So far, no clear genotype-phenotype correlation could be detected in patients with NR5A1 mutations. However, in patients with severe forms of 46,XY DSD, previously described mutations are mostly missense mutations in the DNA-binding region (including its accessory DNA-binding domain) or in the ligand-binding domain as well as nonsense mutations leading to severe changes of the protein (8,10,16,21,30,31,32,33,36,37,38,39).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

“…The phenotypic spectrum has been extended, involving not only ambiguous genitalia and hypospadias due to gonadal dysgenesis (8,9,10), but also vanishing testis syndrome (11), isolated hypoplastic penis (12) and male infertility (13,14). Moreover, NR5A1 mutations were also found in 46,XX females with premature ovarian failure and primary ovarian insufficiency (15,16,17,18,19). Altogether, NR5A1 mutations have emerged as being the most frequent cause (6.5-15%) of different phenotypes of 46,XY DSD in Western countries.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development

Tantawy

Mazen

Soliman

et al. 2014

European Journal of Endocrinology

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Objective: Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamicpituitary-gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD. Design: Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum. Methods: Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected. Results: Three novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Mü llerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism. Conclusion: We identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5-15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure.

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Longitudinal hormonal evaluation in a patient with disorder of sexual development, 46,XY karyotype and one NR5A1 mutation

Pedace

Laino

Preziosi

et al. 2014

American J of Med Genetics Pt A

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Steroidogenic factor 1 (encoded by the NR5A1 gene) is a critical regulator of reproduction, controlling transcription of key genes involved in sexual dimorphism. To date, NR5A1 variants have been found in individuals with a 46,XY karyotype and gonadal dysgenesis, as well as with a wide spectrum of genital anomalies and, in some patients, with adrenal insufficiency. We describe evolution of gonadal function, from the neonatal period to puberty, in a patient with a 46,XY karyotype, a disorder of sexual development, and a mutation (c.691_699dupCTGCAGCTG) in the NR5A1 gene. The patient, ascertained at birth due to ambiguous genitalia, showed normal values of plasma testosterone in the late neonatal period. Evaluation of the hormonal profile over time indicated severe tubular testicular hypofunction suggestive for a 46,XY disorder of gonadal development. A comprehensive review of published reports of 46,XY and disordered sexual development related to the NR5A1 gene confirmed the clinical and hormonal variability in patients with NR5A1 mutations. Analysis of multiple data allowed us to define the most common features associated with NR5A1 mutations. We further confirmed the indication to perform NR5A1 screening in patients with 46,XY karyotype and disordered sexual development even when Müllerian structures appear to be absent and plasma testosterone levels are within the normal range for age.

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Ten Novel Mutations in the NR5A1 Gene Cause Disordered Sex Development in 46,XY and Ovarian Insufficiency in 46,XX Individuals

Cited by 116 publications

References 42 publications

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

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

Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development

Longitudinal hormonal evaluation in a patient with disorder of sexual development, 46,XY karyotype and one NR5A1 mutation

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