A5018038134- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Sexual Differentiation and Disorders
- Urological Disorders and Treatments
- Sperm and Testicular Function
- Reproductive Biology and Fertility
- Animal Genetics and Reproduction
- Renal and related cancers
- Chromosomal and Genetic Variations
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Urologic and reproductive health conditions
- Epigenetics and DNA Methylation
- Hypothalamic control of reproductive hormones
- Hormonal and reproductive studies
- Growth Hormone and Insulin-like Growth Factors
- Genetic Syndromes and Imprinting
- Prenatal Screening and Diagnostics
- Ovarian function and disorders
- Genetic diversity and population structure
- Testicular diseases and treatments
- Genomic variations and chromosomal abnormalities
- RNA regulation and disease
- Genomics and Phylogenetic Studies
- Folate and B Vitamins Research
- Wnt/β-catenin signaling in development and cancer
Institut Pasteur
2016-2025
Centre National de la Recherche Scientifique
2016-2024
Biologie du Développement et Cellules Souches
2022-2024
Laboratoire de Biologie du Développement
2022-2024
Centre de Gestion Scientifique
2024
Université Paris Cité
2021-2023
Institut de Génétique Humaine
2017
Human Genetic of Infectious Diseases
2014
Université de Montpellier
2012
Molina Center for Energy and the Environment
2012
The genetic causes of nonsyndromic ovarian insufficiency are largely unknown. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator genes involved in the hypothalamic-pituitary-steroidogenic axis. Mutation 46,XY disorders sex development, with or without adrenal failure, but growing experimental evidence from studies mice suggests role for this development and function as well.
One in seven couples worldwide are infertile, and male factor infertility accounts for approximately 30%–50% of these cases. Although many genes known to be essential gametogenesis, there surprisingly few monogenic mutations that have been conclusively demonstrated cause human spermatogenic failure. A nuclear receptor, NR5A1 (also called steroidogenic 1), is a key transcriptional regulator involved the hypothalamic-pituitary-steroidogenic axis, it expressed tissue developing adult gonad....
Approximately 1 of every 250 newborns has some abnormality genital and/or gonadal development. However, a specific molecular cause is identified in only 20% these cases disorder sex development (DSD). We family French origin presenting with 46,XY DSD and congenital heart disease. Sequencing the ORF GATA4 heterozygous missense mutation (p.Gly221Arg) conserved N-terminal zinc finger GATA4. This was not observed 450 ancestry-matched control individuals. The compromised ability protein to bind...
Cell lineages of the early human gonad commit to one two mutually antagonistic organogenetic fates, testis or ovary. Some individuals with a 46,XX karyotype develop testes ovotestes (testicular ovotesticular disorder sex development; TDSD/OTDSD), due presence testis-determining gene, SRY Other rare complex syndromic forms TDSD/OTDSD are associated mutations in pro-ovarian genes that repress development (e.g. WNT4); however, genetic cause more common non-syndromic is unknown. Steroidogenic...
Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks canalize development down one pathway while actively repressing other. However, in contrast to testis formation, gene pathways governing ovary have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization testicular/ovotesticular...
Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis partly opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development inhibiting SRY-SOX9-FGF9. molecular basis this mutual antagonism unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target RSPO1-mediated inhibition, required for in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal...
Significance Sex development involves a precise spatiotemporal expression and interactions of numerous genetic factors, including the WT1 (Wilms tumor 1) gene. Complete partial loss-of-function variants are associated with 46,XY disorders/differences sex (DSD). Some 46,XX individuals develop testis in absence testis-determining gene SRY . We describe genotype/phenotype association where impacting C-terminal zinc finger (ZF4) cause individuals. XX mice carrying pathogenic variant ZF4 display...
During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence an appropriate, accessible vitro system is major obstacle understanding mechanisms sex-determination/DSDs. Here, we describe protocols for differentiation mouse human pluripotent cells progenitors....
In recent years, considerable advances have been made in our understanding of genetics mammalian gonad development; however, the underlying genetic aetiology majority patients with 46,XY disorders sex development (DSD) still remains unknown. Based on mouse models, it has hypothesized that haploinsufficiency Friend GATA 2 (FOG2) gene could lead to gonadal dysgenesis specific inbred backgrounds. Using whole exome sequencing, we identified independent missense mutations FOG2 two dysgenesis. One...
Background Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum 46,XY DSD (Disorder Sex Development) phenotypes including severe forms hypospadias. Methodology/Principal Findings We evaluated frequency mutations large series patients presenting and Based on their clinical presentation 77 were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external...
SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but role humans unknown. Here, we show that expressed somatic cells early developing gonad human influences sex determination. We identified two individuals with 46, XY disorders/differences development (DSD) chromosomal rearrangements encompassing locus a third individual DSD missense mutation SOX8. In vitro functional assays indicate this...
XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients 46,XY and all testicular syndrome (TRS) is unknown. We performed exome and/or Sanger sequencing 145 DSD unknown including TRS. Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which essential ribosome...
Background The clinical profile and genetics of individuals with Disorders/Differences Sex Development (DSD) has not been reported in Ukraine. Materials Methods We established the Ukrainian DSD Register identified 682 patients. This cohort includes, 357 patients (52.3% [303 Turner syndrome)] sex chromosome DSD, 119 (17.5%) 46,XY 206 (30.2%) 46,XX DSD. Patients congenital adrenal hyperplasia (CAH, n=185) were excluded from further studies. Fluorescence situ hybridization (FISH) was performed...
Anorchia is defined as the absence of testes in a 46,XY individual with male phenotype. The cause unknown.We evaluated clinical and biological presentation, family histories 26 boys anorchia, sequenced their SRY, NR5A1, INSL3, MAMLD1 genes T222P variant for LGR8.No patient had any associated congenital anomaly. At birth, were palpable bilaterally or unilaterally 13 cases not 7; one presented bilateral testicular torsion immediately after birth. basal plasma concentrations anti-Müllerian...
Disorders of Sex Development (DSD) are a heterogeneous group disorders affecting gonad and/or genito‐urinary tract development and usually the endocrine‐reproductive system. A genetic diagnosis is made in only around 20% these cases. The causes 46,XX‐ SRY negative testicular DSD as well ovotesticular poorly defined. Duplications involving region located ∼600 kb upstream SOX9 , key gene testis development, were reported several cases 46,XX DSD. Recent studies have narrowed this down to 78...
In this review we will consider the gene mutations responsible for non-syndromic forms of disorders sex development (DSD) and how recent genetic findings are providing insights into mechanism determination. High-throughput sequencing technologies having a major impact on our understanding basis rare human disorders, including DSD. The study DSD is progressively revealing subtle differences in genetics sex-determining system between mouse human. This plasticity pathway apparent (a) difference...
Pituitary stalk interruption syndrome (PSIS) and holoprosencephaly (HPE) are congenital midline defects. Rare mutations in the sonic hedgehog (SHH) signaling gene CDON have recently been reported patients with HPE. To report a unique case of PSIS maternally inherited nonsense mutation SHH protein CDON. We performed exome sequencing on PSIS. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) an ancestry-matched control panel were screened upon identification mutation....