The p.G146A and p.P125P Polymorphisms in the Steroidogenic Factor-1 &lt;b&gt;&lt;i&gt;(SF-1)&lt;/i&gt;&lt;/b&gt; Gene Do Not Affect the Risk for Hypospadias in Caucasians

Adamović, Tatjana; Chen, Y; Thai, Hanh T T; Zhang, X; Markljung, Ellen; Zhao, Shidou; Nordenskjöld, Agneta

doi:10.1159/000343782

Cited by 17 publications

(13 citation statements)

References 56 publications

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“…Similar to our functional assays, Arg313Cys showed reduced transactivation on the promoters of the AMH and CYP11A1 genes [37]. Although Arg313 is located in the highly conserved helix 5 of the ligand-binding domain, this same position has also been described for an Arg313His change (c.838G>A) in males with hypospadias [38], [39]. Thus, position Arg313 of SF-1 may be a hot spot for mutations.…”

Section: Discussionsupporting

confidence: 84%

Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

et al. 2014

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ContextHuman NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus.ObjectiveTo characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance.Patients5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency.MethodsSF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3).ResultsTwo novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI.ConclusionsGlu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.

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Section: Discussionsupporting

confidence: 84%

Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

et al. 2014

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“…However, the relative importance of different NR5A1 polymorphisms in hypospadias may depend on ethnicity. Variants in NR5A1 were frequently associated with hypospadias in Chinese patients, but not in Swedish Caucasians [Adamovic et al, 2012]. Two novel NR5A1 mutations with aberrant biological activity were also found in Egyptian patients [Tantawy et al, 2014] (table 2).…”

Section: Genes Implicated In Testis Development Masculinisation and mentioning

confidence: 99%

The Genetic and Environmental Factors Underlying Hypospadias

Bouty

Ayers

Pask

et al. 2015

Sex Dev

160

137

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Hypospadias results from a failure of urethral closure in the male phallus and affects 1 in 200-300 boys. It is thought to be due to a combination of genetic and environmental factors. The development of the penis progresses in 2 stages: an initial hormone-independent phase and a secondary hormone-dependent phase. Here, we review the molecular pathways that contribute to each of these stages, drawing on studies from both human and mouse models. Hypospadias can occur when normal development of the phallus is disrupted, and we provide evidence that mutations in genes underlying this developmental process are causative. Finally, we discuss the environmental factors that may contribute to hypospadias and their potential immediate and transgenerational epigenetic impacts.

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“…However, the father of the proband, who showed the same polymorphism, was not affected by any reproductive disorder, supporting other evidence that Gly146Ala polymorphism leaves transcriptional activity unaltered [15,26]. Recently, analysis of a large case series and controls concluded that no association between Gly146Ala polymorphism and hypospadias is operative, at least in Caucasians [29]. Thus, its causative role remains doubtful.…”

Section: Discussionmentioning

confidence: 60%

NR5A1 Gene Mutations: Clinical, Endocrine and Genetic Features in Two Girls with 46,XY Disorder of Sex Development

Bertelloni

Dati²,

Baldinotti³

et al. 2014

Horm Res Paediatr

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Background: Steroidogenic factor 1, encoded by the NR5A1 gene, is a key regulator of endocrine function within the hypothalamic-pituitary-steroidogenic axis. Both homozygous, compound heterozygous and heterozygous mutations in the NR5A1 gene may determine 46,XY disorders of sex development (DSD). Patients and Methods:NR5A1 gene sequencing was performed in a cohort of 6 patients with 46,XY DSD without specific diagnosis. Results: Heterozygous NR5A1 gene mutations were found in 2 girls, aged 0.5 years and 14 years. The older girl harbored the c.250C>T transition in exon 4 (p.Arg84Cys), previously reported in a Japanese girl. The younger girl presented a de novo novel exon 6 heterozygous frameshift mutation (c.1074dupG) in codon 359 associated with the p.Gly146Ala polymorphism the latter inherited from her father. This baby showed severe impairment of androgen secretion from the first months of life. Overt adrenal insufficiency did not occur, but the older girl showed subnormal cortisol peak after ACTH stimulation. Conclusions:NR5A1 gene mutations are a relatively frequent cause of 46,XY DSD in humans. Clear indications for management of these individuals remain elusive, mainly when diagnosis is made in infancy. Long-term monitoring of adrenal function should be recommended.

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The p.G146A and p.P125P Polymorphisms in the Steroidogenic Factor-1 <b><i>(SF-1)</i></b> Gene Do Not Affect the Risk for Hypospadias in Caucasians

Cited by 17 publications

References 56 publications

Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

The Genetic and Environmental Factors Underlying Hypospadias

NR5A1 Gene Mutations: Clinical, Endocrine and Genetic Features in Two Girls with 46,XY Disorder of Sex Development

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