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European Journal of Human Genetics :... Oct 2023Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare...
Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.
Topics: Animals; Humans; Abnormalities, Multiple; COUP Transcription Factor II; Heart Defects, Congenital; Hernias, Diaphragmatic, Congenital; Intellectual Disability; Muscle Hypotonia; Syndrome
PubMed: 37500725
DOI: 10.1038/s41431-023-01434-5 -
BioRxiv : the Preprint Server For... Jun 2024The microbiome is increasingly recognized to shape many aspects of its host biology and is a key determinant of health and disease. The microbiome may influence...
BACKGROUND
The microbiome is increasingly recognized to shape many aspects of its host biology and is a key determinant of health and disease. The microbiome may influence transmission of pathogens by their vectors, such as mosquitoes or aquatic snails. We previously sequenced the bacterial 16S V4 ribosomal DNA of the hemolymph (blood) of spp. snails, one of the vectors of the human blood fluke schistosome. We showed that snail hemolymph harbored an abundant and diverse microbiome. This microbiome is distinct from the water environment and can discriminate snail species and populations. As hemolymph bathes snail organs, we then investigated the heterogeneity of the microbiome in these organs.
RESULTS
We dissected ten snails for each of two different species ( and ) and collected their organs (ovotestis, hepatopancreas, gut, and stomach). We also ground in liquid nitrogen four whole snails of each species. We sampled the water in which the snails were living (environmental controls). Sequencing the 16S V4 rDNA revealed organ-specific microbiomes. These microbiomes harbored a lower diversity than the hemolymph microbiome, and the whole-snail microbiome. The organ microbiomes tend to cluster by physiological function. In addition, we showed that the whole-snail microbiome is more similar to hemolymph microbiome.
CONCLUSIONS
These results are critical for future work on snail microbiomes and show the necessity of sampling individual organ microbiomes to provide a complete description of snail microbiomes.
PubMed: 38915569
DOI: 10.1101/2024.06.11.598555 -
Animals : An Open Access Journal From... Sep 2020Impaired fertility associated with disorders of sex development (DSDs) due to genetic causes in dogs are more and more frequently reported. Affected dogs are usually of...
Impaired fertility associated with disorders of sex development (DSDs) due to genetic causes in dogs are more and more frequently reported. Affected dogs are usually of specific breeds thus representing a cause of economic losses for breeders. The aim of this research is to report the clinical, cytogenetic and molecular genetic findings of four XX -negative DSD dog cases. All the subjects showed a female aspect and the presence of an enlarged clitoris with a penis bone. Morphopathological analyses performed in three of the four cases showed the presence of testes in two cases and ovotestis in another. Conventional and R-banded cytogenetic techniques were applied showing that no chromosome abnormalities were involved in these DSDs. CGH arrays show the presence of 11 copy number variations (CNVs), one of which is a duplication of 458 Kb comprising the genomic region between base 17,503,928 and base 17,962,221 of chromosome 9 (CanFam3 genome assembly). This CNV, confirmed also by qPCR, includes the promoter region of gene and could explain the observed phenotype.
PubMed: 32947906
DOI: 10.3390/ani10091667 -
Regulatory mechanism of LncRNAs in gonadal differentiation of hermaphroditic fish, Monopterus albus.Biology of Sex Differences Oct 2023Monopterus albus is a hermaphroditic fish with sex reversal from ovaries to testes via the ovotestes in the process of gonadal development, but the molecular mechanism...
BACKGROUND
Monopterus albus is a hermaphroditic fish with sex reversal from ovaries to testes via the ovotestes in the process of gonadal development, but the molecular mechanism of the sex reversal was unknown.
METHODS
We produced transcriptomes containing mRNAs and lncRNAs in the crucial stages of the gonad, including the ovary, ovotestis and testis. The expression of the crucial lncRNAs and their target genes was detected using qRT‒PCR and in situ hybridization. The methylation level and activity of the lncRNA promoter were analysed by applying bisulfite sequencing PCR and dual-luciferase reporter assays, respectively.
RESULTS
This effort revealed that gonadal development was a dynamic expression change. Regulatory networks of lncRNAs and their target genes were constructed through integrated analysis of lncRNA and mRNA data. The expression and DNA methylation of the lncRNAs MSTRG.38036 and MSTRG.12998 and their target genes Psmβ8 and Ptk2β were detected in developing gonads and sex reversal gonads. The results showed that lncRNAs and their target genes exhibited consistent expression profiles and that the DNA methylation levels were negatively regulated lncRNA expression. Furthermore, we found that Ptk2β probably regulates cyp19a1 expression via the Ptk2β/EGFR/STAT3 pathway to reprogram sex differentiation.
CONCLUSIONS
This study provides novel insight from lncRNA to explore the potential molecular mechanism by which DNA methylation regulates lncRNA expression to facilitate target gene transcription to reprogram sex differentiation in M. albus, which will also enrich the sex differentiation mechanism of teleosts.
Topics: Male; Animals; Female; RNA, Long Noncoding; Gonads; Ovary; Testis; Sex Differentiation; Smegmamorpha
PubMed: 37880697
DOI: 10.1186/s13293-023-00559-y -
Scientific Reports Mar 2022Fish are amongst vertebrates the group with the highest diversity of known sex-determining genes. Particularly, the genus Oryzias is a suitable taxon to understand how...
Fish are amongst vertebrates the group with the highest diversity of known sex-determining genes. Particularly, the genus Oryzias is a suitable taxon to understand how different sex determination genetic networks evolved in closely related species. Two closely related species, O. latipes and O. curvinotus, do not only share the same XX/XY sex chromosome system, but also the same male sex-determining gene, dmrt1bY. We performed whole mRNA transcriptomes and morphology analyses of the gonads of hybrids resulting from reciprocal crosses between O. latipes and O. curvinotus. XY male hybrids, presenting meiotic arrest and no production of sperm were sterile, and about 30% of the XY hybrids underwent male-to-female sex reversal. Both XX and XY hybrid females exhibited reduced fertility and developed ovotestis while aging. Transcriptome data showed that male-related genes are upregulated in the XX and XY female hybrids. The transcriptomes of both types of female and of the male gonads are characterized by upregulation of meiosis and germ cell differentiation genes. Differences in the parental species in the downstream pathways of sexual development could explain sex reversal, sterility, and the development of intersex gonads in the hybrids. We hypothesize that male-to-female sex reversal may be connected to a different development time between species at which dmrt1bY expression starts. Our results provide molecular clues for the proximate mechanisms of hybrid incompatibility and Haldane's rule.
Topics: Animals; Female; Gonads; Male; Oryzias; Sex Chromosomes; Sex Determination Processes; Testis
PubMed: 35354874
DOI: 10.1038/s41598-022-09314-6 -
International Journal of Molecular... May 2022Germline stem cells (GSCs) are a group of unique adult stem cells in gonads that act as important transmitters for genetic information. Donor GSCs have been used to...
Germline stem cells (GSCs) are a group of unique adult stem cells in gonads that act as important transmitters for genetic information. Donor GSCs have been used to produce offspring by transplantation in fisheries. In this study, we successfully isolated and enriched GSCs from the ovary, ovotestis, and testis of , one of the most important breeding freshwater fishes in China. Transcriptome comparison assay suggests that a distinct molecular signature exists in each type of GSC, and that different signaling activities are required for the maintenance of distinct GSCs. Functional analysis shows that fGSCs can successfully colonize and contribute to the germline cell lineage of a host zebrafish gonad after transplantation. Finally, we describe a simple feeder-free method for the isolation and enrichment of GSCs that can contribute to the germline cell lineage of zebrafish embryos and generate the germline chimeras after transplantation.
Topics: Adult Stem Cells; Animals; Female; Germ Cells; Gonads; Male; Sex Determination Processes; Zebrafish
PubMed: 35682541
DOI: 10.3390/ijms23115861 -
Hormone Research in Paediatrics 2023Ovotesticular disorder/difference of sex development (DSD) refers to the co-presence of testicular and ovarian tissue in one individual. Childhood management is... (Review)
Review
BACKGROUND
Ovotesticular disorder/difference of sex development (DSD) refers to the co-presence of testicular and ovarian tissue in one individual. Childhood management is challenging as there are many uncertainties regarding etiology, gonadal function, and gender outcome.
SUMMARY
Ovotesticular DSD should mainly be considered in 46,XX children with atypical genitalia and normal adrenal steroid profiles. Various underlying genetic mechanisms have been described. Histological assessment of ovotestes requires expert revision and has many pitfalls. Neonatal sex assignment is essential, but as gender outcome is unpredictable, this should be regarded as provisional until a stable gender identity has developed. Therefore, it is crucial not to perform any irreversible medical or surgical procedure in affected individuals until adolescents can give their full informed consent. Gonadal function mostly allows for spontaneous pubertal development; however, fertility is compromised, especially in boys. Specific long-term outcome data for ovotesticular DSD are lacking but can be extrapolated from studies in other DSD populations.
KEY MESSAGES
Management of ovotesticular DSD has changed in recent years, prioritizing the child's future right for autonomy and self-determination. The benefits and pitfalls of this new approach have not been documented yet and require intensive monitoring on an international scale.
Topics: Infant, Newborn; Child; Adolescent; Humans; Male; Female; Ovotesticular Disorders of Sex Development; Gender Identity; Genitalia; Sexual Development; Genetic Background; Disorders of Sex Development
PubMed: 34469891
DOI: 10.1159/000519323 -
Cureus Dec 2020Ovotesticular disorder or true hermaphroditism is defined as the presence of both ovarian and testicular tissues in the same individual irrespective of the patient's...
Ovotesticular disorder or true hermaphroditism is defined as the presence of both ovarian and testicular tissues in the same individual irrespective of the patient's karyotype. Ovotesticular disorder represents 5% of disorders of sex development. Cases of true hermaphroditism must be treated like men or women based on their age, external genitalia and the orientation of the patient. Here we report a case of true hermaphroditism which was diagnosed with seminoma on histopathological examination. The patient underwent orchiectomy, followed by two cycles of chemotherapy.
PubMed: 33489542
DOI: 10.7759/cureus.12130 -
Marine Pollution Bulletin Oct 202217α-ethinylestradiol (EE2) is an anthropogenic estrogen that is widely used for hormone therapy and oral contraceptives. It was reported that EE2 exposure induced...
17α-ethinylestradiol (EE2) is an anthropogenic estrogen that is widely used for hormone therapy and oral contraceptives. It was reported that EE2 exposure induced reproductive impairments through processes affecting reproduction behavior and inducing ovotestis. However, the effects of continuous EE2 exposure on the reproductive performance remain largely unknown. In this study, adult marine medaka fish (Oryzias melastigma) were exposed to EE2 (85 ng/L) for one (F) and two (F) generations. Our results indicate that continuous EE2 exposure reduced fecundity and sperm motility. The testicular transcriptome, followed by bioinformatic analysis revealed the dysregulation of pathways related to steroidogenesis, sperm motility, and reproductive system development. Collectively, our findings indicate that continuous EE2 exposure directly affected sperm quality via the alteration of steroidogenesis and dysregulation of reproductive system development. The identified key factors including DNM1, PINK1, PDE7B, and SLC12A7 can serve as biomarkers to assess EE2-reduced sperm motility.
Topics: Animals; Biomarkers; Contraceptives, Oral; Estrogens; Ethinyl Estradiol; Female; Male; Oryzias; Protein Kinases; Semen; Sperm Motility; Spermatozoa; Symporters; Water Pollutants, Chemical
PubMed: 36084614
DOI: 10.1016/j.marpolbul.2022.114093 -
Journal of Pediatric Urology Jan 2024The presence of an ovotestis is a rare difference of sex development. The diagnosis can be difficult with the gold standard being the presence of both testicular cords...
INTRODUCTION
The presence of an ovotestis is a rare difference of sex development. The diagnosis can be difficult with the gold standard being the presence of both testicular cords and ovarian follicles within the same gonad.
OBJECTIVE
Herein we describe two new markers of ovotesticular syndrome: ovotesticular cords and ovotesticular follicles.
STUDY DESIGN
Twenty human gonads with a previous diagnosis of ovotestis were re-stained with markers for testicular cords (SOX9, TSPY, SALL4, DDX4, cP450, AR, α-actin) and ovarian tissue (FOXL2, SALL4, DDX4). Ovotesticular cords were defined as structures expressing both testicular Sertoli cell marker (SOX9) and an ovarian follicular cell marker (FOXL2), and in Y chromosome positive specimens, TSPY-positive testicular germ cells. Ovotesticular follicles were defined as a hybrid ovarian follicle containing FOXL2-positive granulosa cells and a central oocyte, but also containing cells expressing the testicular Sertoli cell marker, SOX9, intermingled within FOXL2-positive granulosa cells and male and female germ cells.
RESULTS
Six of twenty ovotestis did not meet our criterion for the diagnosis of ovotestis lacking the histologic evidence of both testicular and ovarian tissue. The remaining 13 patients in which 14 separate specimens were evaluated, contained ovotestis defined by the presence of testicular cords and ovarian follicles. Eleven of the 14 ovotestis specimens (79 %) contained ovotesticular cords. Four of 11 ovotestis specimens (36 %) contained ovotesticular follicles.
DISCUSSION
We recommend using eight immunohistochemical markers to diagnose an ovotestis: 1) SOX9, TSPY, SALL4, DDX4, cytochrome P450, AR, smooth muscle α-actin for the testicular component and FOXL2 and SALL4, DDX4 for the ovarian component. SOX9 and TSPY (useful only in the presence of a Y karyotype) are specific testicular markers and FOXL2 the only specific ovarian marker. We found ovotesticular cords and ovotesticular follicles in both human bipolar and mixed ovotestis specimens both with and without the presence of the Y chromosome. The clinical significance of ovotesticular cords and follicles remains unknown. We did not observe any obvious abnormalities in cellular architecture with the juxtaposition of testicular cells and ovarian cells.
CONCLUSION
We have identified two new structures in humans with ovotestis, ovotesticular cords and ovotesticular follicles (Figure), which appears to be additional markers to facilitate the diagnosis of ovotesticular gonads.
PubMed: 38218629
DOI: 10.1016/j.jpurol.2023.12.016