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.

scholarly journals Disorders of Sex Development in Individuals Harbouring MAMLD1 Variants: WES and Interactome Evidence of Oligogenic Inheritance

2020 ◽  
Vol 11 ◽  
Author(s):  
Lele Li ◽  
Fenqi Gao ◽  
Lijun Fan ◽  
Chang Su ◽  
Xuejun Liang ◽  
...  
Keyword(s):  
Sexual Development ◽  
Disorders Of Sex Development ◽  
Specific Gene ◽  
Causative Role ◽  
Sex Development ◽  
Whole Exome ◽  
Clinical Series ◽  
Oligogenic Inheritance ◽  
Mode Of Inheritance

Mastermind-like domain-containing 1 (MAMLD1) has been shown to play an important role in the process of sexual development and is associated with 46,XY disorders of sex development (DSDs). However, the causative role of MAMLD1 variations in DSDs remains disputable. In this study, we have described a clinical series on children from unrelated families with 46,XY DSD harbouring MAMLD1 variants. Whole exome sequencing (WES) was performed for each patient. WES data were filtered using common tools and disease customisation algorithms, including comparison against lists of known and candidate MAMLD1-related and DSD-related genes. Lastly, we investigated the hypothesis that MAMLD1-related DSD may follow an oligogenic mode of inheritance. Forty-three potentially deleterious/candidate variants of 18 genes (RET, CDH23, MYO7A, NOTCH2, MAML1, MAML2, CYP1A1, WNT9B, GLI2, GLI3, MAML3, WNT9A, FRAS1, PIK3R3, FREM2, PTPN11, EVC, and FLNA) were identified, which may have contributed to the patient phenotypes. MYO7A was the most commonly identified gene. Specific gene combinations were also identified. In the interactome analysis, MAMLD1 exhibited direct connection with MAML1/2/3 and NOTCH1/2. Through NOTCH1/2, the following eight genes were shown to be associated with MAMLD1:WNT9A/9B, GLI2/3, RET, FLNA, PTPN11, and EYA1. Our findings provide further evidence that individuals with MAMLD1-related 46,XY DSD could carry two or more variants of known DSD-related genes, and the phenotypic outcome of affected individuals might be determined by multiple genes.

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 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.

scholarly journals Long-Range Regulation of Key Sex Determination Genes

2021 ◽  
pp. 1-21
Author(s):  
Roberta Migale ◽  
Michelle Neumann ◽  
Robin Lovell-Badge
Keyword(s):  
Sex Determination ◽  
Long Range ◽  
Current Knowledge ◽  
Disorders Of Sex Development ◽  
Sexually Dimorphic ◽  
Protein Coding ◽  
Sex Development ◽  
Human Disorders ◽  
The Many

The development of sexually dimorphic gonads is a unique process that starts with the specification of the bipotential genital ridges and culminates with the development of fully differentiated ovaries and testes in females and males, respectively. Research on sex determination has been mostly focused on the identification of sex determination genes, the majority of which encode for proteins and specifically transcription factors such as SOX9 in the testes and FOXL2 in the ovaries. Our understanding of which factors may be critical for sex determination have benefited from the study of human disorders of sex development (DSD) and animal models, such as the mouse and the goat, as these often replicate the same phenotypes observed in humans when mutations or chromosomic rearrangements arise in protein-coding genes. Despite the advances made so far in explaining the role of key factors such as SRY, SOX9, and FOXL2 and the genes they control, what may regulate these factors upstream is not entirely understood, often resulting in the inability to correctly diagnose DSD patients. The role of non-coding DNA, which represents 98% of the human genome, in sex determination has only recently begun to be fully appreciated. In this review, we summarize the current knowledge on the long-range regulation of 2 important sex determination genes, <i>SOX9</i> and <i>FOXL2</i>, and discuss the challenges that lie ahead and the many avenues of research yet to be explored in the sex determination field.

scholarly journals Disorders of Sex Development: Classification, Review, and Impact on Fertility

2020 ◽  
Vol 9 (11) ◽  
pp. 3555
Author(s):  
Pedro Acién ◽  
Maribel Acién
Keyword(s):  
Sex Determination ◽  
Klinefelter Syndrome ◽  
Sex Differentiation ◽  
Disorders Of Sex Development ◽  
Androgen Excess ◽  
Adrenal Steroid ◽  
Sex Development ◽  
Male Phenotype ◽  
Kallman Syndrome

In this review, the elements included in both sex determination and sex differentiation are briefly analyzed, exposing the pathophysiological and clinical classification of disorders or anomalies of sex development. Anomalies in sex determination without sex ambiguity include gonadal dysgenesis, polysomies, male XX, and Klinefelter syndrome (dysgenesis and polysomies with a female phenotype; and sex reversal and Klinefelter with a male phenotype). Other infertility situations could also be included here as minor degrees of dysgenesis. Anomalies in sex determination with sex ambiguity should (usually) include testicular dysgenesis and ovotesticular disorders. Among the anomalies in sex differentiation, we include: (1) males with androgen deficiency (MAD) that correspond to those individuals whose karyotype and gonads are male (XY and testes), but the phenotype can be female due to different hormonal abnormalities. (2) females with androgen excess (FAE); these patients have ovaries and a 46,XX karyotype, but present varying degrees of external genital virilization as a result of an enzyme abnormality that affects adrenal steroid biosynthesis and leads to congenital adrenal hyperplasia; less frequently, this can be caused by iatrogenia or tumors. (3) Kallman syndrome. All of these anomalies are reviewed and analyzed herein, as well as related fertility problems.

scholarly journals In-vitro cellular reprogramming to model gonad development and its disorders

2021 ◽  
Author(s):  
Nitzan Gonen ◽  
Caroline Eozenou ◽  
Richard Mitter ◽  
Andreia Bernardo ◽  
Almira Chervova ◽  
...  
Keyword(s):  
Sex Determination ◽  
Gonad Development ◽  
Disorders Of Sex Development ◽  
Cellular Reprogramming ◽  
Tubule Formation ◽  
Sex Development ◽  
Human Disorders ◽  
Induced Pluripotent

During embryonic development, mutually antagonistic signaling cascades determine the fate of the bipotential gonad towards a testicular or ovarian identity. Errors in this process result in human Disorders of Sex Development (DSDs), where there is discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in-vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells towards gonadal progenitors. Transcriptomic analysis reveals that the in-vitro-derived murine gonadal cells are equivalent to E11.5 in-vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete AMH, migrate and form tubular structures. The cells derived from a 46,XY DSD female hiPSCs, carrying a NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR/Cas9-mediated correction of the variant rescued the phenotype. This is a robust tool to understand mechanisms of sex-determination and model DSDs.

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