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

Takasawa, Kei; Igarashi, Maki; Ono, Makoto; Takemoto, Akira; Takada, Shuji; Yamataka, Atsuyuki; Ogata, Tsutomu; Morio, Tomohiro; Fukami, Maki; Kashimada, Kenichi

doi:10.1159/000485868

Cited by 13 publications

(15 citation statements)

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“…Incomplete penetrance and variable expressivity are well established features of NR5A1 ‐associated disorders, this is because adreno‐gonadal development is exquisitely sensitive to changes in NR5A1 gene dosage (Val, Martinez‐Barbera, & Swain, ) and may be subject to genetic or environmental modifiers. A recent paper reported a 46,XX sibling pair each with the heterozygous NR5A1 p.Arg92Trp variant displaying markedly different phenotypes, which indicates that environment is an important modifier (Takasawa et al., ). Furthermore, these variants are absent or at low frequency in large population databases (e.g., gnomAD) and individuals with the NR5A1 p.Arg92Trp variant have diverse ethnic backgrounds, including African, Hispanic, European, and Asian, suggesting that the variable phenotypic expressivity observed is not a product of founder effect or genetic background.…”

Section: Discussionmentioning

confidence: 99%

“…During gonadal differentiation, NR5A1 is involved in both activation and repression of the testis pathway. Variants in the NR5A1 gene can cause a wide variety of DSDs including 46,XY gonadal dysgenesis, 46,XX premature ovarian insufficiency, and recently a single variant (p.Arg92Trp) has been implicated in 46,XX (ovo)testicular DSD (Baetens et al., ; Bashamboo et al., ; Domenice et al., ; Igarashi et al., ; Takasawa et al., ). The exact mechanism by which this variant activates testis development in a 46,XX individual remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Despite these known causes, SRY‐negative 46,XX (ovo)testicular DSDs have a diagnostic rate much lower than that of other DSDs (Eggers et al., ) highlighting a need to identify novel genes or genetic variants underlying these DSDs. Recently, five reports have described a recurrent heterozygous variant in the Nuclear Receptor Subfamily 5 Group A Member 1 ( NR5A1 ) gene (c.274C>T; p.Arg92Trp) in 12 cases of 46,XX (ovo)testicular DSD (Baetens et al., ; Bashamboo et al., ; Domenice et al., ; Igarashi et al., ; Takasawa et al., ), although the underlying mechanism for how this NR5A1 variant causes sex reversal in these cases is still unclear. NR5A1, or steroidogenic factor‐1 (SF1, Ad4BP; MIM# 184757), is a nuclear receptor transcription factor with a key regulatory role in development of the hypothalamus–pituitary–gonadal and hypothalamus–pituitary–adrenal axes (Morohashi et al., ; Parker et al., ; Val, Lefrancois‐Martinez, Veyssiere, & Martinez, ), and thus in the development of the male and female gonads (reviewed in Ferraz‐de‐Souza, Lin, & Achermann, ; Lin et al., ).…”

Section: Introductionmentioning

confidence: 99%

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NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

et al. 2018

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Several recent reports have described a missense variant in the gene NR5A1 (c.274C>T; p.Arg92Trp) in a significant number of 46,XX ovotesticular or testicular disorders of sex development (DSDs) cases. The affected residue falls within the DNA‐binding domain of the NR5A1 protein, however the exact mechanism by which it causes testicular development in 46,XX individuals remains unclear. We have screened a cohort of 26 patients with 46,XX (ovo)testicular DSD and identified three unrelated individuals with this NR5A1 variant (p.Arg92Trp), as well as one patient with a novel NR5A1 variant (c.779C>T; p.Ala260Val). We examined the functional effect of these changes, finding that while protein levels and localization were unaffected, variant NR5A1 proteins repress the WNT signaling pathway and have less ability to upregulate the anti‐testis gene NR0B1 . These findings highlight how NR5A1 variants impact ovarian differentiation across multiple pathways, resulting in a switch from ovarian to testis development in genetic females.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

et al. 2018

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“…The incidence of complete gonadal dysgenesis is estimated to be 1:80000 in newborns ( Michala et al, 2008 ). One gene, NR5A1 gene located on chr 9q33.3, has emerged play a major role as a common genetic cause in 10–20% of 46, XY DSD cases in the last few years ( Suntharalingham et al, 2015 ; Takasawa et al, 2017 ), it encodes steroidogenic factor-1 (SF-1). SF-1 is a key regulator of steroidogenesis and reproductive development that controls several steps of adrenal and gonadal development.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, in addition to causing 46, XY DSDs and adrenal dysfunction, missense mutations in NR5A1 were identified as a cause of 46, XX testicular/ovotesticular disorders of sexual development ( Baetens et al, 2017 ; Igarashi et al, 2017 ; Takasawa et al, 2017 ). While a genotype–phenotype relationship has not been established to date, approximately 120 NR5A1 mutations have been documented in the Human Gene Mutation Database 1 .…”

Section: Introductionmentioning

confidence: 99%

Phenotype and Molecular Characterizations of 30 Children From China With NR5A1 Mutations

2018

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Background: Patients harboring NR5A1 mutations have a wide spectrum of phenotypes.Objective: To investigate the phenotype of patients with NR5A1 gene mutations from a 30 Chinese patient cohort.Methods: We reported the clinical features of children with NR5A1 gene mutations and compared them between two groups of patients with social genders of male (boys group) and female (girls group).Results: Thirty patients with NR5A1 mutations ranging from 2 months to 17 years of age were studied. There were 11 boys and 19 girls who were identified when they visited the hospital. The patients were verified as having testes without a uterus and ovaries by B-mode ultrasound. There was no difference between boys and girls in terms of the Prader stage (p = 0.086), but the position of the testes was higher in girls than in boys (p = 0.013). The patients’ average height is −0.43 SDS according to the normal boys’ height with SDS (while their average target height was 0.07 SDS). However, there was no such difference between boys and girls (p > 0.05). Although the basal LH and post-hCG testosterone (T) levels were not different (p > 0.05), but the basal FSH level, LH/FSH ratio, and INHB level were decreased in girls (p = 0.002; p = 0.001; p = 0.006). All of the mothers of the patients reported to have normal pregnancies. We found 24 patients (80%) with de novo mutations in the NR5A1 gene; 5 patients had inherited mutations from their mothers, and one inherited from the father. Only the mothers of patients 16 and 18 showed premature ovarian failure at the time of reporting. Among 26 disease associated mutations, 14 novel mutations that have been reported the first time and p.R87C is the most common Among the other 12 had had been reported,the p.R313C is the most common.Conclusion: Patients with 46, XY NR5A1 mutations presented a wide spectrum of external genitalia characteristics and severe Sertoli cell impairment. The p.R87C and p.R313C mutations appeared to be common (10%) in this group, and 14 new mutations were identified, improving our understanding the genotype phenotype correlations.

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Pubertal development in 46,XY patients with NR5A1 mutations

et al. 2021

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Purpose Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. Methods We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. Results Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. Conclusion Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.

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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

Cited by 13 publications

References 12 publications

NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

NR5A1gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

Phenotype and Molecular Characterizations of 30 Children From China With NR5A1 Mutations

Pubertal development in 46,XY patients with NR5A1 mutations

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