Molecular mechanisms associated with 46,XX disorders of sex development

2016 ◽  
Vol 130 (6) ◽  
pp. 421-432 ◽  
Author(s):  
Ingrid Knarston ◽  
Katie Ayers ◽  
Andrew Sinclair
Keyword(s):  
Molecular Mechanisms ◽  
Ovarian Development ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Female Gonad ◽  
Ovarian Differentiation ◽  
Sex Development ◽  
Human Disorders ◽  
Genetic Mechanisms

In the female gonad, distinct signalling pathways activate ovarian differentiation while repressing the formation of testes. Human disorders of sex development (DSDs), such as 46,XX DSDs, can arise when this signalling is aberrant. Here we review the current understanding of the genetic mechanisms that control gonadal development, with particular emphasis on those that drive or inhibit ovarian differentiation. We discuss how disruption to these molecular pathways can lead to 46,XX disorders of ovarian development. Finally, we look at recently characterized novel genes and pathways that contribute and speculate how advances in technology will aid in further characterization of normal and disrupted human ovarian development.

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

Nuclear receptor action involved with sex differentiation

2003 ◽  
Vol 75 (11-12) ◽  
pp. 1771-1784 ◽  
Author(s):  
I. A. Hughes ◽  
Howard Martin ◽  
Jarmo Jääskeläinen ◽  
C. L. Acerini
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Reproductive Tract ◽  
Sex Differentiation ◽  
Disorders Of Sex Development ◽  
Nuclear Hormone Receptor ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Sex Development ◽  
Sequence Of Events

Sex determination and differentiation in the male is an orderly sequence of events coordinated by genetic and hormonal factors operating in a time- and concentration-dependent manner. The constitutive sex in mammals is female. Disorders of fetal sex development have provided the means to identify testis-determining genes and the molecular mechanisms of hormone action. Thus, the androgen receptor, a nuclear hormone receptor critical for androgen-induced male sex differentiation, displays unique intra-receptor and protein-protein interactions which, when disturbed, can result in extreme forms of sex reversal. Polymorphic variants are associated with milder disorders of sex development. Against this genetic background, endocrine active substances may further contribute to the underlying causes of an increase in male reproductive tract disorders.

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.

scholarly journals Disorders of sex development: Genetic characterization of a patient cohort

2019 ◽  
Author(s):  
Mary Garc�a-Acero ◽  
Olga Moreno-Ni�o ◽  
Fernando Su�rez-Obando ◽  
M�nica Molina ◽  
Mar�a Manotas ◽  
...  
Keyword(s):  
Genetic Characterization ◽  
Disorders Of Sex Development ◽  
Patient Cohort ◽  
Sex Development

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 Mouse models of human disorders of sex development (DSD)

2017 ◽  
Vol 145 ◽  
pp. S148
Author(s):  
Abigail Harris ◽  
Pam Siggers ◽  
Nick Warr ◽  
Gwenn Carre ◽  
Anu Bashamboo ◽  
...  
Keyword(s):  
Mouse Models ◽  
Disorders Of Sex Development ◽  
Sex Development ◽  
Human Disorders
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