NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

2019 ◽  
Vol 13 (5-6) ◽  
pp. 258-263
Author(s):  
Maria F. Faienza ◽  
Mariangela Chiarito ◽  
Fulvia Baldinotti ◽  
Domenico Canale ◽  
Carmela Savino ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Cell Function ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Reproductive Function ◽  
In Silico Analysis ◽  
Gonadal Development ◽  
Gene Variants ◽  
Psychological Outcome ◽  
Sex Development

<i>NR5A1</i> (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous <i>NR5A1 </i>mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with <i>NR5A1</i> genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous <i>NR5A1</i> genetic variants. In the boys, pathogenetic<i> NR5A1</i> gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that <i>NR5A1 </i>gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with <i>NR5A1</i> mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward.

scholarly journals Clinical and molecular characteristics of patients with 46,XY DSD due to NR5A1 gene mutations

2020 ◽  
Vol 66 (3) ◽  
pp. 62-69
Author(s):  
Natalia Yu. Kalinchenko ◽  
Anna A. Kolodkina ◽  
Nadezda Y. Raygorodskaya ◽  
Anatoly N. Tiulpakov
Keyword(s):  
Gonadal Dysgenesis ◽  
Case Reports ◽  
Molecular Genetic ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Gonadal Development ◽  
Molecular Genetic Analysis ◽  
Molecular Characteristics ◽  
Sex Development ◽  
Reproductive Axis

Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 310 Russian patients with 46,XY disorders of sex development (DSD). Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described. We have not found any phenotype-genotype correlations and any clinical and laboratory markers that would allow to suspect this type of before conducting molecular genetic analysis.

scholarly journals NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

2018 ◽  
Vol 40 (2) ◽  
pp. 207-216 ◽  
Author(s):  
Ingrid M. Knarston ◽  
Gorjana Robevska ◽  
Jocelyn A van den Bergen ◽  
Stefanie Eggers ◽  
Brittany Croft ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Disorders Of Sex Development ◽  
Gene Variants ◽  
Sex Development

scholarly journals Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development

2019 ◽  
Vol 56 (7) ◽  
pp. 434-443 ◽  
Author(s):  
Katie Ayers ◽  
Jocelyn van den Bergen ◽  
Gorjana Robevska ◽  
Nurin Listyasari ◽  
Jamal Raza ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Disorders Of Sex Development ◽  
Culture Method ◽  
Significant Loss ◽  
Subcellular Localisation ◽  
Gene Variants ◽  
Gene Variant ◽  
Clinical Interpretation ◽  
Sex Development ◽  
Desert Hedgehog

BackgroundDesert hedgehog (DHH) gene variants are known to cause 46,XY differences/disorders of sex development (DSD). We have identified six patients with 46,XY DSD with seven novel DHH gene variants. Many of these variants were classified as variants of uncertain significance due to their heterozygosity or associated milder phenotype. To assess variant pathogenicity and to refine the spectrum of DSDs associated with this gene, we have carried out the first reported functional testing of DHH gene variant activity.MethodsA cell co-culture method was used to assess DHH variant induction of Hedgehog signalling in cultured Leydig cells. Protein expression and subcellular localisation were also assessed for DHH variants using western blot and immunofluorescence.ResultsOur co-culture method provided a robust read-out of DHH gene variant activity, which correlated closely with patient phenotype severity. While biallelic DHH variants from patients with gonadal dysgenesis showed significant loss of activity, variants found as heterozygous in patients with milder phenotypes had no loss of activity when tested with a wild type allele. Taking these functional results into account improved clinical interpretation.ConclusionOur findings suggest heterozygous DHH gene variants are unlikely to cause DSD, reaffirming that DHH is an autosomal recessive cause of 46,XY gonadal dysgenesis. Functional characterisation of novel DHH variants improves variant interpretation, leading to greater confidence in patient reporting and clinical management.

scholarly journals Non-Syndromic 46,XY Disorders of Sex Development

2018 ◽  
Vol 18 (1) ◽  
pp. 35-41
Author(s):  
J Gecz ◽  
J Breza ◽  
P Banovcin
Keyword(s):  
Genetic Testing ◽  
Slovak Republic ◽  
Molecular Genetic ◽  
Disorders Of Sex Development ◽  
Gene Variants ◽  
Molecular Genetic Testing ◽  
The Past ◽  
Sex Development

Abstract Non-syndromic 46,XY DSD (disorders of sex development) represent a phenotypically diversiform group of disorders. We focus on the association between gene variants and the most frequent types of non-syndromic 46,XY DSD, options of molecular genetic testing which has surely taken its place in diagnostics of DSD in the past couple of years. We emphasize the need of molecular genetic testing in individuals with non-syndromic 46,XY DSD in Slovak Republic.

Functional characterization of five NR5A1 gene mutations found in patients with 46,XY disorders of sex development

2017 ◽  
Vol 39 (1) ◽  
pp. 114-123 ◽  
Author(s):  
Helena Fabbri-Scallet ◽  
Maricilda Palandi de Mello ◽  
Gil Guerra-Júnior ◽  
Andréa Trevas Maciel-Guerra ◽  
Juliana Gabriel Ribeiro de Andrade ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Sex Development

scholarly journals Clinical and molecular spectrum of 46, XY disorders of sex development that harbour MAMLD1 variations: Case series and review of literature

2020 ◽  
Author(s):  
Li Lele ◽  
Lijun Fan ◽  
Fenqi Gao ◽  
Di Wu ◽  
Chunxiu Gong
Keyword(s):  
Protein Function ◽  
Clinical Manifestations ◽  
Disorders Of Sex Development ◽  
Case Series ◽  
In Silico Analysis ◽  
Causative Role ◽  
Causative Gene ◽  
Sex Development ◽  
Clinical Series

Abstract Background Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46, XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46, XY DSD. Cases of 46, XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children’s Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated.Results Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.A356X, p.G152X, and p.G124X) and six missense (p.P334S, p.S662A, p.A421P,p.T992I, p.P542S, and p.A927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662A, and p.A927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function.Conclusion Patients with 46, XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46, XY DSD.

Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development

2015 ◽  
Vol 28 (11-12) ◽  
Author(s):  
Vehap Topcu ◽  
Hatice Ilgin-Ruhi ◽  
Zeynep Siklar ◽  
Halil Gurhan Karabulut ◽  
Merih Berberoglu ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Sequence Analysis ◽  
Receptor Gene ◽  
Correct Diagnosis ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Androgen Receptor Gene ◽  
Direct Sequence ◽  
Sex Development ◽  
Direct Sequence Analysis

AbstractAndrogen receptor (We direct sequenced all eight exons of theWe detectedDespite the fact that T/DHT ratio is frequently used in diagnosis of AIS, lack of precisely determined cutoffs compromises correct diagnosis. Hence, depending on clinical and biochemical findings solely may delay correct diagnosis. Direct sequence analysis of the

scholarly journals Wnt Signaling in Ovarian Development Inhibits Sf1 Activation of Sox9 via the Tesco Enhancer

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 901-912 ◽  
Author(s):  
Pascal Bernard ◽  
Janelle Ryan ◽  
Helena Sim ◽  
Daniel P. Czech ◽  
Andrew H. Sinclair ◽  
...  
Keyword(s):  
Sertoli Cell ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Ovary Development ◽  
Specific Gene ◽  
Loss Of Function ◽  
Sox9 Expression ◽  
Protein Levels ◽  
Sex Development ◽  
Culture Models

Genome analysis of patients with disorders of sex development, and gain- and loss-of-function studies in mice indicate that gonadal development is regulated by opposing signals. In females, the Wnt/β-catenin canonical pathway blocks testicular differentiation by repressing the expression of the Sertoli cell-specific gene Sox9 by an unknown mechanism. Using cell and embryonic gonad culture models, we show that activation of the Wnt/β-catenin pathway inhibits the expression of Sox9 and Amh, whereas mRNA and protein levels of Sry and steroidogenic factor 1 (Sf1), two key transcriptional regulators of Sox9, are not altered. Ectopic activation of Wnt/β-catenin signaling in male gonads led to a loss of Sf1 binding to the Tesco enhancer and absent Sox9 expression that we also observed in wild-type ovaries. Moreover, ectopic Wnt/β-catenin signaling induced the expression of the female somatic cell markers, Bmp2 and Rspo1, as a likely consequence of Sox9 loss. Wnt/β-catenin signaling in XY gonads did not, however, affect gene expression of the steroidogenic Leydig cell Sf1 target gene, Cyp11a1, or Sf1 binding to the Cyp11a1 promoter. Our data support a model in ovary development whereby activation of β-catenin prevents Sf1 binding to the Sox9 enhancer, thereby inhibiting Sox9 expression and Sertoli cell differentiation.

Morphological analysis of testicles in cats with disorders of sex development

2017 ◽  
Vol 20 (1) ◽  
pp. 123-131 ◽  
Author(s):  
S. Dzimira ◽  
W. Nizanski ◽  
J.A. Madej
Keyword(s):  
Blood Vessels ◽  
Polyclonal Antibodies ◽  
S100 Protein ◽  
Smooth Muscles ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Control Group ◽  
Histological Structure ◽  
Sex Development ◽  
Hematoxylin And Eosin

Abstract Disorders of sex development (DSD) are rare in cats. They can be caused by chromosomal aberrations, gene mutations or other undefined factors. The aim of the present study was to compare the histological structure and immunohistochemical reactivity of testes in cats with DSD and in healthy cats. The research material consisted of the gonads of four cats - phenotypic males with an incorrect structure of the reproductive system. The control group consisted of the testes of four healthy cats - routinely castrated phenotypical males. The material was fixed with formalin and embedded in paraffin; the sections were stained with hematoxylin and eosin. The immunohistochemical investigation were performed using monoclonal and polyclonal antibodies directed against desmin, vimentin, actin of smooth muscles, S100 protein and MCM3 protein. The results obtained allow concluding that the testes of cats with DSD differed in certain respects, mainly in the number of blood vessels, from the normal testes. Moreover, the results of immunohistochemical examination indicate that in the testes of cats with DSD the number of supporting cells is lower, the amount of interstitial cells is comparable and spermatogenesis is correct es compared to those determined in the control gonads. The number of blood vessels in cats with DSD is reduced by about 30%. It confirms the recommendations for castration of these animals in order to eliminate the potential inheritance of sex development disorders.

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