The Molecular Basis of Gonadal Development and Disorders of Sex Development

2011 ◽  
pp. 1-9 ◽  
Author(s):  
Stefan White ◽  
Andrew Sinclair
Keyword(s):  
Molecular Basis ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Sex Development

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.

scholarly journals Genetic Analysis for the Diagnosis of Disorders of Sexual Development in Indonesia

2016 ◽  
Vol 2 (2) ◽  
pp. 44
Author(s):  
Sultana MH Faradz
Keyword(s):  
Sexual Development ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Gonadal Development ◽  
Androgen Insensitivity Syndrome ◽  
Medical Professionals ◽  
Adrenal Hyperplasia ◽  
Disorders Of Sexual Development ◽  
Sex Development

Disorders of sex development (DSD) is defined by congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical, while in clinical practice this term means any abnormality of the external genitalia. DSD patients have been managed by a multidisciplinary gender team in our center as collaboration between Dr. Kariadi province referral hospital and Faculty of Medicine Diponegoro University. Diagnosis should be established by specific physical examination hormonal, chromosomal and DNA studies; and imaging for most of the cases depending on indication.Since 2004 the involvement of molecular and cytogenetic analysis so far can diagnosed many of the DSD cases. Most of the genetically proven cases were Congenital Adrenal hyperplasia, Androgen Insensitivity syndrome and sex chromosomal DSD that lead abnormal gonadal development.  Many of them remain undiagnosed, further testing such as advanced DNA study should be carried out in collaboration with other center in overseas.The novel genes were found in some cases that contributed for the management of DSD.  Information for medical professionals, patients, family members and community about the availability and necessity of DSD diagnosis should be delivered to improve DSD management and patient quality of life.

Targeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development

2021 ◽  
pp. 1-19
Author(s):  
Gabby Atlas ◽  
Rajini Sreenivasan ◽  
Andrew Sinclair
Keyword(s):  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Regulatory Elements ◽  
Gonadal Development ◽  
Comparative Genomic ◽  
Enhancer Activity ◽  
Sex Development ◽  
Genomic Regions

Disorders of sex development (DSD) are a complex group of conditions with highly variable clinical phenotypes, most often caused by failure of gonadal development. DSD are estimated to occur in around 1.7% of all live births. Whilst the understanding of genes involved in gonad development has increased exponentially, approximately 50% of patients with a DSD remain without a genetic diagnosis, possibly implicating non-coding genomic regions instead. Here, we review how variants in the non-coding genome of DSD patients can be identified using techniques such as array comparative genomic hybridization (CGH) to detect copy number variants (CNVs), and more recently, whole genome sequencing (WGS). Once a CNV in a patient’s non-coding genome is identified, putative regulatory elements such as enhancers need to be determined within these vast genomic regions. We will review the available online tools and databases that can be used to refine regions with potential enhancer activity based on chromosomal accessibility, histone modifications, transcription factor binding site analysis, chromatin conformation, and disease association. We will also review the current in vitro and in vivo techniques available to demonstrate the functionality of the identified enhancers. The review concludes with a clinical update on the enhancers linked to DSD.

Ovotesticular disorders of sex development in FGF9 mouse models of human synostosis syndromes

2020 ◽  
Vol 29 (13) ◽  
pp. 2148-2161
Author(s):  
Anthony D Bird ◽  
Brittany M Croft ◽  
Masayo Harada ◽  
Lingyun Tang ◽  
Liang Zhao ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Testis Development ◽  
Sex Development ◽  
Mouse Mutants ◽  
Skeletal Defects ◽  
Xy Sex Reversal

Abstract In mice, male sex determination depends on FGF9 signalling via FGFR2c in the bipotential gonads to maintain the expression of the key testis gene SOX9. In humans, however, while FGFR2 mutations have been linked to 46,XY disorders of sex development (DSD), the role of FGF9 is unresolved. The only reported pathogenic mutations in human FGF9, FGF9S99N and FGF9R62G, are dominant and result in craniosynostosis (fusion of cranial sutures) or multiple synostoses (fusion of limb joints). Whether these synostosis-causing FGF9 mutations impact upon gonadal development and DSD etiology has not been explored. We therefore examined embryonic gonads in the well-characterized Fgf9 missense mouse mutants, Fgf9S99N and Fgf9N143T, which phenocopy the skeletal defects of FGF9S99N and FGF9R62G variants, respectively. XY Fgf9S99N/S99N and XY Fgf9N143T/N143T fetal mouse gonads showed severely disorganized testis cords and partial XY sex reversal at 12.5 days post coitum (dpc), suggesting loss of FGF9 function. By 15.5 dpc, testis development in both mutants had partly recovered. Mitotic analysis in vivo and in vitro suggested that the testicular phenotypes in these mutants arise in part through reduced proliferation of the gonadal supporting cells. These data raise the possibility that human FGF9 mutations causative for dominant skeletal conditions can also lead to loss of FGF9 function in the developing testis, at least in mice. Our data suggest that, in humans, testis development is largely tolerant of deleterious FGF9 mutations which lead to skeletal defects, thus offering an explanation as to why XY DSDs are rare in patients with pathogenic FGF9 variants.

scholarly journals Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

2020 ◽  
Vol 21 (7) ◽  
pp. 2282 ◽  
Author(s):  
Nathalia Lisboa Gomes ◽  
Tarini Chetty ◽  
Anne Jorgensen ◽  
Rod T Mitchell
Keyword(s):  
Fertility Preservation ◽  
Gene Networks ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Testicular Development ◽  
Clear Understanding ◽  
Sex Development ◽  
Future Fertility ◽  
The Individual ◽  
The Impact

Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.

scholarly journals The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD)

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Maria Luisa Granada ◽  
Laura Audí
Keyword(s):  
Multidisciplinary Team ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Abnormal Development ◽  
Sex Characteristics ◽  
Fetal Life ◽  
Sex Development ◽  
Male Sex

Abstract Objectives The development of female or male sex characteristics occurs during fetal life, when the genetic, gonadal, and internal and external genital sex is determined (female or male). Any discordance among sex determination and differentiation stages results in differences/disorders of sex development (DSD), which are classified based on the sex chromosomes found on the karyotype. Content This chapter addresses the physiological mechanisms that determine the development of female or male sex characteristics during fetal life, provides a general classification of DSD, and offers guidance for clinical, biochemical, and genetic diagnosis, which must be established by a multidisciplinary team. Biochemical studies should include general biochemistry, steroid and peptide hormone testing either at baseline or by stimulation testing. The genetic study should start with the determination of the karyotype, followed by a molecular study of the 46,XX or 46,XY karyotypes for the identification of candidate genes. Summary 46,XX DSD include an abnormal gonadal development (dysgenesis, ovotestes, or testes), an androgen excess (the most frequent) of fetal, fetoplacental, or maternal origin and an abnormal development of the internal genitalia. Biochemical and genetic markers are specific for each group. Outlook Diagnosis of DSD requires the involvement of a multidisciplinary team coordinated by a clinician, including a service of biochemistry, clinical, and molecular genetic testing, radiology and imaging, and a service of pathological anatomy.

scholarly journals SRY and NR5A1 gene mutation in Algerian children and adolescents with DSD and testicular dysgenesis

2021 ◽  
Vol 21 (3) ◽  
pp. 1491-1497
Author(s):  
Naouel Kherouatou-Chaoui ◽  
Djalila Chellat-Rezgoune ◽  
Mohamed Larbi Rezgoune ◽  
Ken Mc Elreavey ◽  
Laaldja Souhem Touabti ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Gonadal Development ◽  
Genetic Alterations ◽  
Peripheral Blood Lymphocytes ◽  
Blood Leukocytes ◽  
Sex Development

Background: In humans, sex determination and differentiation is genetically controlled. Disorders of sex development (DSD) result in anomalies of the development of the external and internal genitalia. Variants in transcription factors such as SRY, NR5A1 and SOX9, can cause changes in gonadal development often associated with ambiguity of the external genitalia. Objectives: This study has been conducted to determine the frequency, types and associated genetic alterations in patients with DSD in the Algerian population. Methods: Thirty patients were included. Based on their clinical presentation, thirteen patients presented with ambiguous external genitalia, thirteen patients presented with hypospadias and four patients presented with bilateral undescended tes- tes. Karyotype analysis was performed on peripheral blood lymphocytes using standard R-banding. DNA was isolated from blood leukocytes for PCR reaction and mutational analysis of SRY and NR5A1 was done by direct sequencing. Results: Most patients with ambiguous genitalia had a 46,XY karyotype. One patient had a deletion of SRY, otherwise no point mutations in SRY or NR5A1 genes were identified. However, a single NR5A1 polymorphism (p.Gly146Ala) in patient with 46,XX DSD has been detected. Conclusions: The absence of mutations in these genes suggests that there are others genes playing an important role in sex development and differentiation. Keywords: DSD; consanguinity; karyotyping; SRY; NR5A1; sequencing.

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.

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