A conserved function of Human DLC3 and Cv-c in testis development.

The identification of genes affecting gonad development is essential to understand the mechanisms causing Variations/Differences in Sex Development (DSD). Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients. We have studied the requirement of Cv-c, the ortholog of DLC3, in gonad development, as well as the functional capacity of DLC3 human variants to rescue gonad defects.

Estrogens: Two nuclear receptors, multiple possibilities.

Much is known about estrogen action in experimental animal models and in human physiology. This article reviews the mechanisms of estrogen activity in animals and humans and the role of its two receptors α and β in terms of structure and mechanisms of action in various tissues in health and in relationship with human pathologies (e.g.

CBX2 in DSD: The Quirky Kid on the Block.

Sex development is an intricate and crucial process in all vertebrates that ensures the continued propagation of genetic diversity within a species, and ultimately their survival. Perturbations in this process can manifest as disorders/differences of sex development (DSD). Various transcriptional networks have been linked to development of the gonad into either male or female, which is actively driven by a set of genes that function in a juxtaposed manner and is maintained through the developmental stages to preserve the final sexual identity.

CBX2-dependent transcriptional landscape: implications for human sex development and its defects.

Sex development, a complex and indispensable process in all vertebrates, has still not been completely elucidated, although new genes involved in sex development are constantly being discovered and characterized. Chromobox Homolog 2 (CBX2) is one of these new additions and has been identified through a 46,XY girl with double heterozygous variants on CBX2.1, causing Differences of Sex Development (DSD).

Pluripotent Cell Models for Gonadal Research.

Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous conditions not as rare as previously thought. Part of the obstacles in proper management of these patients is due to an incomplete understanding of the genetics programs and molecular pathways involved in sex development and DSD.

A Human Gonadal Cell Model From Induced Pluripotent Stem Cells.

Sertoli cells are main players in the male gonads development and their study may shed light on 46,XY disorders of sex development (DSD). Mature primary Sertoli cells are incapable of proliferating in prolonged cultures and the available Sertoli cell models have several limitations since they derive from mouse or human cancer tissues. We differentiated human fibroblasts (HFs)-derived induced pluripotent stem cells into Sertoli-like cells (SLC) and, in order to characterize this new Sertoli cell model, we performed gene expression analyses by NextGeneration Sequencing techniques.

Early-Onset Complete Ovarian Failure and Lack of Puberty in a Woman With Mutated Estrogen Receptor β (ESR2).

Context: Estrogen resistance due to mutations in the estrogen receptor α gene (ESR1) has been described in men and women and is characterized by osteoporosis, delayed bone age and continuous growth in adulthood, and delayed puberty and multiple ovarian cysts in women. Although mutations in the estrogen receptor β gene ESR2 were found in 46, XY patients with differences of sex development, no genetic variants of ESR2 were linked to gonadal defects in women.

Settings And Patient: Here we describe a 16-year-old female patient who came to our tertiary care hospital with complete lack of estrogen action, as demonstrated by absent breast development, primary amenorrhea, and osteoporosis, resembling patients with ESR1 mutation.

Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development.

Background: One of the defining moments of human life occurs early during embryonic development, when individuals sexually differentiate into either male or female. Perturbation of this process can lead to disorders/differences of sex development (DSD). Chromobox protein homolog 2 (CBX2) has two distinct isoforms, CBX2.

A novel DAX-1 (NR0B1) mutation in a boy with X-linked adrenal hypoplasia congenita.

Background: X-linked adrenal hypoplasia congenita (AHC) is caused by mutations in DAX-1 (NR0B1) playing a key role in adrenal and reproductive development.

Case Presentation: Herein we report a 2.5-year-old boy who presented with acute adrenal failure.

Human Sex Development: from Basic Science to Clinical Practice and Back.

The process of sexual differentiation is central for the reproduction of almost all metazoan, and therefore for the maintenance of multicellular organisms. In sex development, we can distinguish two different processes¸ sex determination, the l decision directing the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development.

Clinical follow-up of the first SF-1 insufficient female patient.

Objective: Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency.

Why boys will be boys and girls will be girls: Human sex development and its defects.

Among the most defining events of an individual's life, is the development of a human embryo into male or a female. The phenotypic sex of an individual depends on the type of gonad that develops in the embryo, a process which itself is determined by the genetic setting of the individual. The development of the gonads is different from any other organ, as they possess the potential to differentiate into two functionally distinct organs, testes, or ovaries.

The Battle of the Sexes: Human Sex Development and Its Disorders.

The process of sexual differentiation is central for reproduction of almost all metazoan and therefore for maintenance of practically all multicellular organisms. In sex development we can distinguish two different processes: First, sex determination is the developmental decision that directs the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development.

Ovarian development and disease: The known and the unexpected.

The idea that the female sexual development happens by default was born in the middle of the last century after Jost carried out his innovative experiments to study the bases of differentiation of the reproductive tract, and found that the female reproductive tract develops even in the absence of any gonad. The term default (passive) attributed to the whole female developmental pathway therefore established itself, even if it was not originally so intended. However, recent developments have demonstrated that ovarian development is an active process.

Effects of Steroid Hormones on Sex Differences in Cerebral Perfusion.

Sex differences in the brain appear to play an important role in the prevalence and progression of various neuropsychiatric disorders, but to date little is known about the cerebral mechanisms underlying these differences. One widely reported finding is that women demonstrate higher cerebral perfusion than men, but the underlying cause of this difference in perfusion is not known. This study investigated the putative role of steroid hormones such as oestradiol, testosterone, and dehydroepiandrosterone sulphate (DHEAS) as underlying factors influencing cerebral perfusion.

Genome-wide identification of CBX2 targets: insights in the human sex development network.

Chromobox homolog 2 (CBX2) is a chromatin modifier that plays an important role in sexual development and its disorders (disorders of sex development [DSD]), yet the exact rank and function of human CBX2 in this pathway remains unclear. Here, we performed large-scale mapping and analysis of in vivo target loci of the protein CBX2 in Sertoli-like NT-2D1 cells, using the DNA adenine methyltransferase identification technique. We identified close to 1600 direct targets for CBX2.

Identification of a SIRT1 mutation in a family with type 1 diabetes.

Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis.

Of marsupials and men: "Backdoor" dihydrotestosterone synthesis in male sexual differentiation.

Following development of the fetal bipotential gonad into a testis, male genital differentiation requires testicular androgens. Fetal Leydig cells produce testosterone that is converted to dihydrotestosterone in genital skin, resulting in labio-scrotal fusion. An alternative 'backdoor' pathway of dihydrotestosterone synthesis that bypasses testosterone has been described in marsupials, but its relevance to human biology has been uncertain.

WNT4, RSPO1, and FOXL2 in sex development.

The idea that the female sexual development happens by default was born in the middle of the last century after Jost performed his innovative experiments to study the bases of differentiation of the reproductive tract and found that the female reproductive tract develops even in the absence of any gonad. The term default (passive) attributed to the whole female developmental pathway, therefore, established itself, even if it was not originally so intended. However, recent developments have demonstrated that ovarian development is an active process.

Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.

Human sexual determination is initiated by a cascade of genes that lead to the development of the fetal gonad. Whereas development of the female external genitalia does not require fetal ovarian hormones, male genital development requires the action of testicular testosterone and its more potent derivative dihydrotestosterone (DHT). The "classic" biosynthetic pathway from cholesterol to testosterone in the testis and the subsequent conversion of testosterone to DHT in genital skin is well established.

Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene.

Context: Aromatase deficiency in women is a rare 46, XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens.

Objective: To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences.

Design And Patient: We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy.

Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome).

In a collaborative study, we investigated four 46,XX adolescent girls with Mayer-Rokitansky-Küster-Hauser syndrome and hyperandrogenism. Molecular analysis of the WNT4 gene permitted us to identify a new mutation (p.A233T).

Control of sex development.

The process of sexual differentiation is central for reproduction of almost all metazoan, and therefore, for maintenance of practically all multicellular organisms. In sex development, we can distinguish two different processes, sex determination, that is the developmental decision that directs the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development.