Heterozygous Missense Mutations in Steroidogenic Factor 1 (SF1/Ad4BP, NR5A1) Are Associated with 46,XY Disorders of Sex Development with Normal Adrenal Function

Lin, Lin; Philibert, Pascal; Ferraz-de-Souza, Bruno; Kelberman, Daniel; Homfray, Tessa; Albanese, Assunta; Molini, V.; Sebire, Neil J.; Einaudi, Silvia; Conway, Gerard S.; Hughes, Ieuan A.; Jameson, J. Larry; Sultan, Charles; Dattani, Mehul; Achermann, John C.

doi:10.1210/jc.2006-1672

Cited by 186 publications

(212 citation statements)

References 40 publications

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“…In vitro activation of CYP11A1 and CYP19 gene promoters by the novel NR5A1 mutant p.Leu358Pro was reduced, in comparison to WT NR5A1 (29% and 18% of WT, respectively). Notably, the degree of transcriptional activity impairment at the CYP11A1 promoter by p.Leu358Pro NR5A1 was comparable to that of the well‐known NR5A1 mutant p.Gly35Glu (Lin et al, 2007) and more severe than p.Arg92Gln (Achermann et al, 2002). Results represent the mean (SEM) for three assays, each performed in triplicate, and shown relative to wild‐type transactivation.…”

Section: Resultsmentioning

confidence: 69%

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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: Resultsmentioning

confidence: 69%

“…Transient gene expression assays were performed using human embryonic kidney TSA‐201 cells to analyze transcriptional activation of murine Cyp11a1 and rat Cyp19 promoters by wild‐type or mutant NR5A1 (Lin et al, 2007) (see Supporting Information).…”

Section: Molecular Analysismentioning

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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“…Although the first three cases (8)(9)(10) presented with adrenal insufficiency, the others had normal adrenal function (11)(12)(13)(14)(15). Moreover, these individuals displayed varying degrees of gonadal dysfunction, with apparently normal ovarian function in a genotypically female patient (10).…”

Section: Introductionmentioning

confidence: 99%

A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency

Reuter¹,

Goji²,

Bingham³

et al. 2007

eur j endocrinol

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Objective: Steroidogenic factor 1 (SF1), officially designated NR5A1, is a nuclear receptor that plays key roles in endocrine development and function. Previous reports of human SF1 mutations revealed a spectrum of phenotypes affecting adrenal function and/or gonadal development and sex differentiation. We present the clinical phenotype and functional effects of a novel SF1 mutation. Patient: The patient is a 22-year-old 46, XY Japanese patient who presented with dysgenetic testes, atrophic vasa deferentia and epididymides, lack of Mü llerian structures, and clitoromegaly. Endocrine studies revealed normal adrenal function. Results: Analysis of the SF1 gene revealed compound heterozygosity for a previously described p.G146A polymorphism and a novel missense mutation (p.R84C) in the accessory DNA-binding domain. The father carried the p.G146A polymorphism and the mother had the p.R84C mutation; both were clinically and reproductively normal. Functional studies demonstrated that the p.R84C SF1 had normal nuclear localization but decreased DNA-binding affinity and transcriptional activity compared with wild-type SF1; it did not exhibit any dominant negative activity. Conclusions: These results describe the human phenotype that results from compound heterozygosity of the p.G146A polymorphism and a novel p.R84C mutation of SF1, thereby extending the spectrum of human SF1 mutations that impair testis development and sex differentiation in a sex-limited manner while preserving normal adrenal function. 157 233-238 European Journal of Endocrinology

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“…Steroidogenic factor-1 (SF1) is a nuclear transcription factor that plays an important part in adrenal and gonadal development, steroidogenesis and reproduction. Lin et al and Reuter et al [10,11] demonstrated that SF1 mutations (SFl/AdBP4/FTZF1, NRSA1) Recently, mutations in genes other than SRY gene were also discovered in patients with complete pure gonadal dysgenesis. Canto and colleagues [12] firstly described the mutations of Desert hedgehog (DHH) gene associated with the presence of 46, XY complete pure gonadal dysgenesis.…”

Section: Discussionmentioning

confidence: 99%