scholarly journals Cis-Regulatory Control of Mammalian Sex Determination

2021 ◽  
pp. 1-18
Author(s):  
Meshi Ridnik ◽  
Stefan Schoenfelder ◽  
Nitzan Gonen
Keyword(s):  
Sex Determination ◽  
Cell Fate ◽  
Developmental Disorders ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Regulatory Elements ◽  
Regulatory Control ◽  
Male Factor ◽  
Cis Acting ◽  
Sex Development

Sex determination is the process by which an initial bipotential gonad adopts either a testicular or ovarian cell fate. The inability to properly complete this process leads to a group of developmental disorders classified as disorders of sex development (DSD). To date, dozens of genes were shown to play roles in mammalian sex determination, and mutations in these genes can cause DSD in humans or gonadal sex reversal/dysfunction in mice. However, exome sequencing currently provides genetic diagnosis for only less than half of DSD patients. This points towards a major role for the non-coding genome during sex determination. In this review, we highlight recent advances in our understanding of non-coding, cis-acting gene regulatory elements and discuss how they may control transcriptional programmes that underpin sex determination in the context of the 3-dimensional folding of chromatin. As a paradigm, we focus on the <i>Sox9</i> gene, a prominent pro-male factor and one of the most extensively studied genes in gonadal cell fate determination.

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.

scholarly journals Transcriptional Regulation of the Y-Linked Mammalian Testis-Determining Gene SRY

2021 ◽  
pp. 1-9
Author(s):  
Naoki Okashita ◽  
Makoto Tachibana
Keyword(s):  
Sex Determination ◽  
Sex Differentiation ◽  
Disorders Of Sex Development ◽  
Sex Reversal ◽  
Cis Acting ◽  
Male Development ◽  
Sex Development ◽  
Epigenetic Modifier ◽  
Male Sex ◽  
Testis Determining Gene

Mammalian male sex differentiation is triggered during embryogenesis by the activation of the Y-linked testis-determining gene <i>SRY</i>. Since insufficient or delayed expression of <i>SRY</i> results in XY gonadal sex reversal, accurate regulation of <i>SRY</i> is critical for male development in XY animals. In humans, dysregulation of <i>SRY</i> may cause disorders of sex development. Mouse <i>Sry</i> is the most intensively studied mammalian model of sex determination. <i>Sry</i> expression is controlled in a spatially and temporally stringent manner. Several transcription factors play a key role in sex determination as trans-acting factors for <i>Sry</i> expression. In addition, recent studies have shown that several epigenetic modifications of <i>Sry</i> are involved in sex determination as cis-acting factors for <i>Sry</i> expression. Herein, we review the current understanding of transcription factor- and epigenetic modifier-mediated regulation of <i>SRY</i>/<i>Sry</i> expression.

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

2021 ◽  
pp. 1-9
Author(s):  
Maria T.M. Ferrari ◽  
Andreia Watanabe ◽  
Thatiane E. da Silva ◽  
Nathalia L. Gomes ◽  
Rafael L. Batista ◽  
...  
Keyword(s):  
Kidney Development ◽  
Wilms Tumor ◽  
Genetic Diagnosis ◽  
Germ Cell Tumors ◽  
Disorders Of Sex Development ◽  
Medical Attention ◽  
Primary Amenorrhea ◽  
Normal Female ◽  
Sex Development ◽  
Pathogenic Variants

Wilms’ tumor suppressor gene 1 (<i>WT1</i>) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of <i>WT1</i> have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between <i>WT1</i> disorders has been frequently observed. New <i>WT1</i> variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic <i>WT1</i> variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of <i>WT1</i> between exons 9 and 10. Two pathogenic missense <i>WT1</i> variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were &#x3c;1 year of age at the time of diagnosis. A novel <i>WT1</i> variant<i>,</i> c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with <i>WT1</i> variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

177. A MECHANISM UNDERLYING DISORDERS OF SEX DEVELOPMENT CAUSED BY DAX1 DUPLICATION

2009 ◽  
Vol 21 (9) ◽  
pp. 95
Author(s):  
L. Ludbrook ◽  
R. Sekido ◽  
R. Lovell-Badge ◽  
V. Harley
Keyword(s):  
Sex Determination ◽  
Disorders Of Sex Development ◽  
Nuclear Hormone Receptor ◽  
Testicular Development ◽  
Transcriptional Level ◽  
Sox9 Expression ◽  
Transgenic Mouse Line ◽  
Sex Development

The DAX1 protein is an orphan nuclear hormone receptor expressed in developing and adult hypothalamic, pituitary, adrenal and gonadal tissues. In humans, duplication of the DAX1 gene at locus Xp21 causes Disorders of Sex Development (DSD), whereby XY individuals develop as females, due to the failure of testicular development. DAX1 acts as a co-factor for nuclear receptor-mediated transcription of steroidogenic genes. In mice, overexpression of a Dax1 transgene causes delayed testis cord formation, a milder phenotype than that seen in human (1). Exactly how DAX1 duplication interferes with typical testicular development is unclear but a ‘window' of DAX1 activity was proposed (2). In order to identify the mechanism of DAX1 action when overexpressed in the developing XY gonad, we have used both in vivo and in vitro approaches. We hypothesised that, when present in excess, DAX1 must repress the action of early testis-forming genes. We investigated the effect of Dax1 over expression, using the Dax1 transgenic mouse line, Dax1812 (1), on expression of Sox9, a critical testis-forming gene. Immunostaining of Dax1812 gonads revealed reduced Sox9 expression, suggesting excess Dax1 antagonises Sox9 upregulation during the early stages of sex determination. To determine whether antagonism of Sox9 was occurring at the transcriptional level we assessed the effect of excess Dax1 on the activity of the Testis-Specific Enhancer of Sox9 (TES), which drives Sox9 transcription in the developing XY gonad (3). In combination, the in vivo and in vitro evidence strongly suggests that Dax1, when present in excess, can repress Sox9 expression through TES and that this repression occurs through inhibition of Steroidogenic Factor-1 activity. With this work we have identified a potential mechanism for disruption of the male-specific sex determination pathway caused by DAX1 duplication and leading to DSD in XY individuals.

scholarly journals ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling

2018 ◽  
Vol 115 (21) ◽  
pp. 5474-5479 ◽  
Author(s):  
Abigail Harris ◽  
Pam Siggers ◽  
Silvia Corrochano ◽  
Nick Warr ◽  
Danielle Sagar ◽  
...  
Keyword(s):  
Sex Determination ◽  
Wnt Signaling ◽  
Disorders Of Sex Development ◽  
Ovary Development ◽  
Sex Development ◽  
Mutual Antagonism ◽  
Testis Determination ◽  
Direct Target ◽  
Canonical Wnt ◽  
Xy Female

Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects. These abnormalities are associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human ZNRF3 variants in very rare cases of XY female presentation. We tested two missense variants and show that these disrupt ZNRF3 activity in both human cell lines and zebrafish embryo assays. Our data identify a testis-determining function for ZNRF3 and indicate a mechanism of direct molecular interaction between two mutually antagonistic organogenetic pathways.

scholarly journals Disorders of sex development: advances in genetic diagnosis and challenges in management

2015 ◽  
pp. 165 ◽  
Author(s):  
Faisal Ahmed ◽  
Andreas Kyriakou ◽  
Edward Tobias ◽  
Angela Lucas-Herald ◽  
Ruth McGowan
Keyword(s):  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Sex Development

scholarly journals Modern opportunities and indications for genetic diagnosis of male infertility

2019 ◽  
pp. 3-15
Author(s):  
Т.М. Сорокина ◽  
О.А. Соловова ◽  
В.Б. Черных
Keyword(s):  
Male Infertility ◽  
Recurrent Miscarriage ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Genomic Analysis ◽  
Copy Number Variations ◽  
Genetic Causes ◽  
Sex Development ◽  
Genetic Examination

Тяжелые формы мужского и женского бесплодия, привычного невынашивания беременности, аномалий формирования пола часто обусловлены генетическими причинами или связаны с генетическими факторами. Медико-генетическое обследование и консультирование пациентов с нарушением репродукции зачастую ограничивается использованием стандартных рутинных исследований, поэтому не позволяет выявить многие наследственные формы репродуктивной патологии. Методы геномного анализа позволяют повысить эффективность диагностики генетически обусловленных нарушений репродукции, вызванных генными мутациями и вариациями числа копий (CNV), но их пока широко не используют в практическое медицине. В статье рассмотрены современные возможности медико-генетического обследования мужчин с нарушением фертильности, а также приведены показания и алгоритмы диагностики генетических причин мужского бесплодия, связанного с различными формами патозооспермии. Evere forms of male and female infertility, recurrent miscarriage, abnormalities in disorders of sex development are often due to genetic causes or are associated with genetic factors. Genetic examination and counseling of patients with reproductive problems is often limited to the use of standard routine techniques, therefore, it is not possible to identify many hereditary forms of reproductive pathology. Genomic analysis methods can improve the diagnosis of genetic reproductive disorders caused by gene mutations and copy number variations (CNVs), but they are not yet widely used in practical medicine. The article discusses the modern possibilities of medical-genetic examination of infertile men with, as well as the indications and diagnostic algorithms for the genetic causes of male infertility associated with various forms of pathozoospermia.

scholarly journals FGF9 is a downstream target of SRY and sufficient to determine male sex fate in ex vivo XX gonad culture

2020 ◽  
Vol 103 (6) ◽  
pp. 1300-1313
Author(s):  
Yi-Han Li ◽  
Tsung-Ming Chen ◽  
Bu-Miin Huang ◽  
Shang-Hsun Yang ◽  
Chia-Ching Wu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Ex Vivo ◽  
Disorders Of Sex Development ◽  
Sex Reversal ◽  
Vital Role ◽  
Loss Of Function ◽  
Downstream Target ◽  
Sex Development ◽  
Male Sex

Abstract Fibroblast growth factor 9 (FGF9) is an autocrine/paracrine growth factor that plays critical roles in embryonic and organ developments and is involved in diverse physiological events. Loss of function of FGF9 exhibits male-to-female sex reversal in the transgenic mouse model and gain of FGF9 copy number was found in human 46, XX sex reversal patient with disorders of sex development. These results suggested that FGF9 plays a vital role in male sex development. Nevertheless, how FGF9/Fgf9 expression is regulated during testis determination remains unclear. In this study, we demonstrated that human and mouse SRY bind to −833 to −821 of human FGF9 and −1010 to −998 of mouse Fgf9, respectively, and control FGF9/Fgf9 mRNA expression. Interestingly, we showed that mouse SRY cooperates with SF1 to regulate Fgf9 expression, whereas human SRY-mediated FGF9 expression is SF1 independent. Furthermore, using an ex vivo gonadal culture system, we showed that FGF9 expression is sufficient to switch cell fate from female to male sex development in 12–16 tail somite XX mouse gonads. Taken together, our findings provide evidence to support the SRY-dependent, fate-determining role of FGF9 in male sex development.

scholarly journals Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

2020 ◽  
Vol 21 (22) ◽  
pp. 8554
Author(s):  
Idoia Martínez de LaPiscina ◽  
Rana AA Mahmoud ◽  
Kay-Sara Sauter ◽  
Isabel Esteva ◽  
Milagros Alonso ◽  
...  
Keyword(s):  
Sex Determination ◽  
Broad Spectrum ◽  
Clinical Characteristics ◽  
Phenotypic Expression ◽  
Disorders Of Sex Development ◽  
Organ Function ◽  
Transactivation Activity ◽  
Sex Development ◽  
Genetic Features ◽  
Mode Of Inheritance

Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation.

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