scholarly journals Mutation Analysis of NR5A1 Encoding Steroidogenic Factor 1 in 77 Patients with 46, XY Disorders of Sex Development (DSD) Including Hypospadias

PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e24117 ◽  
Author(s):  
Slimane Allali ◽  
Jean-Baptiste Muller ◽  
Raja Brauner ◽  
Diana Lourenço ◽  
Radia Boudjenah ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Disorders Of Sex Development ◽  
Steroidogenic Factor 1 ◽  
Sex Development

scholarly journals 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

2014 ◽  
Vol 170 (5) ◽  
pp. 759-767 ◽  
Author(s):  
Sally Tantawy ◽  
Inas Mazen ◽  
Hala Soliman ◽  
Ghada Anwar ◽  
Abeer Atef ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Direct Sequencing ◽  
Disorders Of Sex Development ◽  
Missense Mutations ◽  
Coding Region ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
Gene Coding ◽  
Future Fertility

ObjectiveSteroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic–pituitary–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.DesignClinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum.MethodsMolecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected.ResultsThree 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-Müllerian 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.ConclusionWe 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.

scholarly journals Mutation Analysis of FOXF2 in Patients with Disorders of Sex Development (DSD) in Combination with Cleft Palate

2008 ◽  
Vol 2 (6) ◽  
pp. 302-308 ◽  
Author(s):  
U. Jochumsen ◽  
R. Werner ◽  
N. Miura ◽  
A. Richter-Unruh ◽  
O. Hiort ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Mutation Analysis ◽  
Disorders Of Sex Development ◽  
Sex Development

scholarly journals The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency

2009 ◽  
Vol 161 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Birgit Köhler ◽  
Lin Lin ◽  
Inas Mazen ◽  
Cigdem Cetindag ◽  
Heike Biebermann ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Mutational Analysis ◽  
Disorders Of Sex Development ◽  
Inhibin B ◽  
Binding Motif ◽  
Undescended Testes ◽  
Gender Assignment ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
Penoscrotal Hypospadias

ObjectiveHypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.Design and methodsMutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network.ResultsHeterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients.ConclusionsSF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.

scholarly journals Multifunctional role of steroidogenic factor 1 and disorders of sex development

2011 ◽  
Vol 55 (8) ◽  
pp. 607-612 ◽  
Author(s):  
Maricilda Palandi de Mello ◽  
Emerson Salvador de Souza França ◽  
Helena Campos Fabbri ◽  
Andréa Trevas Maciel-Guerra ◽  
Gil Guerra-Júnior
Keyword(s):  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Gonadal Differentiation ◽  
Steroidogenic Factor 1 ◽  
Functional Roles ◽  
Secondary Sexual Characteristics ◽  
Delayed Onset ◽  
Sex Development ◽  
Sexual Characteristics

Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1.

167. MUTANT STEROIDOGENIC FACTOR-1 FROM PATIENTS WITH DISORDERS OF SEX DEVELOPMENT SHOW REDUCED ACTIVATION OF THE TESTIS-SPECIFIC ENHANCER OF SOX9

2009 ◽  
Vol 21 (9) ◽  
pp. 85
Author(s):  
L. Ludbrook ◽  
B. Fisher ◽  
V. Harley
Keyword(s):  
Critical Role ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Nuclear Hormone Receptor ◽  
Steroidogenic Factor 1 ◽  
Enhancer Element ◽  
Sex Development ◽  
Naturally Occurring ◽  
Synergistic Activation ◽  
Severe Impairment

The orphan nuclear hormone receptor Steroidogenic Factor 1 (SF1; NR5A1) is expressed throughout hypothalamic, pituitary, gonadal and adrenal tissues. Naturally occurring human mutations combined with mouse knockout models have revealed a critical role for SF1 as a transcription factor at multiple stages during gonadal development and during development of the adrenal. Missense mutation or truncation to SF1 in XY humans cause Disorders of Sex Development (DSD) with variable phenotypes. The precise mechanisms of SF1 action that fail in human DSD are not fully determined. This work aimed to utilise naturally occurring DSD-causing mutations in SF1 to increase our understanding of the sex determining function of SF1 in the developing male gonad. Recent work by others (1) identified SOX9 as a key target gene of SF1 during testis determination. SF1 activates Sox9 through a testis-specific enhancer element, termed TES. We tested the abilities of eleven clinical SF1 mutations to activate TES in reporter assays in HEK293T cells. Eight of the eleven SF1 mutants showed considerably reduced activation of TES compared to WT SF1. Furthermore, all mutations causing moderate to severe DSD phenotypes correlated with a more severe impairment of TES activation. In addition, all eleven of the mutants showed reduced synergistic activation of TES in co-transfection with the testis-determining co-factor SRY. Overall, this biochemical analysis of the function of mutant SF1 from DSD patients suggests that a failure of SOX9 up regulation, due to reduced activation of TES during testis development, could be the primary cause of the DSD in some patients with SF1 mutations.

scholarly journals The first clinical presentation of disorders of sex development 46 XY due to mutation in Steroidogenic factor 1 (SF1) in Russian Literature

2016 ◽  
Vol 62 (1) ◽  
pp. 55-59
Author(s):  
Natalia Yur'evna Kalinchenko ◽  
Tatiana Aleksandrovna Anosova ◽  
Vitaliy Alekseevich Ioutsi ◽  
Anatoly Nikolaevich Tiulpakov
Keyword(s):  
Molecular Genetic ◽  
Critical Role ◽  
Disorders Of Sex Development ◽  
Russian Literature ◽  
Molecular Genetic Analysis ◽  
Heterozygous Mutation ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
And Function ◽  
First Time

Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a critical role in different processes of sex development. Homozygous mutations in SF1 result in adrenal failure and complete testicular disgenesis in 46,XY individuals. According to recent studies heterozygous mutations in SF1 are associated with milder phenotype: they are found in children with 46,XY disorders of sex development (DSD) but with apparently normal adrenal structure and function. Here we present for the first time in Russian literature a case of SF1 deficiency. Molecular genetic analysis of NR5A1 gene revealed a novel heterozygous mutation c.951delC p.H317QfsX17. This clinical case demonstrates the importance of molecular genetic studies in DSD 46,XY, especially severe forms.

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