Three New SF-1 &lt;i&gt;(NR5A1) &lt;/i&gt;Gene Mutations in Two Unrelated Families with Multiple Affected Members: Within-Family Variability in 46,XY Subjects and Low Ovarian Reserve in Fertile 46,XX Subjects

Warman, Diana M.; Costanzo, Mariana; Marino, Roxana; Berensztein, Esperanza; Galeano, Jesica; Ramírez, Pablo; Saraco, Nora; Baquedano, María Sonia; Ciaccio, Marta; Guercio, Gabriela; Chaler, Eduardo; Maceiras, Mercedes; Lazzatti, Juan Manuel; Bailez, Marcela; Rivarola, Marco A.; Belgorosky, Alicia

doi:10.1159/000320029

Cited by 58 publications

(74 citation statements)

References 75 publications

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“…Warman et al reported a family with six members harbouring a heterozygous NR5A1 hinge region mutation (p.Tyr183X) and displaying a wide range of different phenotypes. Three affected members had isolated hypospadias, two of whom were severe perineal and one was mild glandular (9). Another case of isolated distal hypospadias carrying a de novo heterozygous missense mutation (p.Arg313Cys) located at the end of the ligand-binding domain of the NR5A1 gene was reported by Allali et al (10) ( Table 2).…”

Section: European Journal Of Endocrinologymentioning

confidence: 89%

“…So far, there is no apparent genotype-phenotype correlation in patients with NR5A1 mutations. 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).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: European Journal Of Endocrinologymentioning

confidence: 89%

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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“…Partial hypogonadotropic hypogonadism, necessitating testosterone supplementation during puberty has been documented in one male patient with penoscrotal hypospadias and a L437Q mutation in the NR5A1 ligand-binding domain (8). Recently, normal pubertal progression, with low Inhibin B but normal LH and FSH concentrations has been reported in two adolescents with a milder phenotype (12). In this study, we report on spontaneous and advanced androgenization in two adolescents who were poorly virilized at birth and sexassigned female, with reassignment to male in one patient at the age of 2 years.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical presentation of patients affected by NR5A1 mutations is very diverse, ranging in 46,XY individuals from phenotypically females with complete gonadal dysgenesis with or without adrenal failure (5)(6)(7)(8)(9)(10) to males with penoscrotal hypospadias (8,11,12) or bilateral anorchia (13). In 46,XX women, NR5A1 mutations have been associated with premature ovarian failure (3).…”

Section: Introductionmentioning

confidence: 99%

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Cools

Hoebeke

Wolffenbuttel

et al. 2012

European Journal of Endocrinology

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Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. Design and methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9TOA, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)_(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function. Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

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“…However, a clear correlation between the location of a mutation, its in vitro functional performance, and the associated phenotype is not observed. Indeed, family members bearing the same NR5A1 mutation may present with variable phenotypes (Warman et al, 2011). …”

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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Three New SF-1 <i>(NR5A1) </i>Gene Mutations in Two Unrelated Families with Multiple Affected Members: Within-Family Variability in 46,XY Subjects and Low Ovarian Reserve in Fertile 46,XX Subjects

Cited by 58 publications

References 75 publications

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

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

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

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

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