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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 -
Cureus Jun 2023A case is reported herein of a true hermaphrodite (TH) with an ovotestis, a uterus, a vagina, and an underdeveloped phallus. The patient was raised by his parents as a...
A case is reported herein of a true hermaphrodite (TH) with an ovotestis, a uterus, a vagina, and an underdeveloped phallus. The patient was raised by his parents as a male, based on the presence of a phallus with ambiguous genitalia. He started experiencing breast enlargement at the age of 14 and menarche by the age of 17. He was reviewed using ultrasound, magnetic resonance imaging of the abdomen, and karyotyping, and the reports showed evidence of Mullerian structures and 46 XX karyotyping. Based on the preferences of the patient and his parents and their psychological outlook toward the male gender, a total mastectomy, hysterectomy, bilateral gonadectomy, and total vaginectomy were performed. This was followed by reconstruction of the male genitalia and supplemented with male hormone replacement therapy. Accordingly, a TH was assigned a male gender.
PubMed: 37425607
DOI: 10.7759/cureus.40104 -
Biomolecules Apr 2023Gonadal development is the first step in human reproduction. Aberrant gonadal development during the fetal period is a major cause of disorders/differences of sex... (Review)
Review
Gonadal development is the first step in human reproduction. Aberrant gonadal development during the fetal period is a major cause of disorders/differences of sex development (DSD). To date, pathogenic variants of three nuclear receptor genes (, , and ) have been reported to cause DSD via atypical testicular development. In this review article, we describe the clinical significance of the variants as the cause of DSD and introduce novel findings from recent studies. variants are associated with 46,XY DSD and 46,XX testicular/ovotesticular DSD. Notably, both 46,XX DSD and 46,XY DSD caused by the variants show remarkable phenotypic variability, to which digenic/oligogenic inheritances potentially contribute. Additionally, we discuss the roles of and in the etiology of DSD. acts as an anti-testicular gene. Duplications containing result in 46,XY DSD, whereas deletions encompassing can underlie 46,XX testicular/ovotesticular DSD. has recently been reported as a causative gene for 46,XX testicular/ovotesticular DSD and possibly for 46,XY DSD, although the role of in gonadal development is unclear. The knowledge about these three nuclear receptors provides novel insights into the molecular networks involved in the gonadal development in human fetuses.
Topics: Humans; Male; Disorder of Sex Development, 46,XY; Mutation; Ovotesticular Disorders of Sex Development; Phenotype; Sexual Development; Testis; Receptors, Cytoplasmic and Nuclear
PubMed: 37189438
DOI: 10.3390/biom13040691 -
PeerJ 2023Dietary ingestion is the main route of exposure to hazardous contaminants in land animals. Cadmium, a high-profile toxic metal, affects living systems at different...
Dietary ingestion is the main route of exposure to hazardous contaminants in land animals. Cadmium, a high-profile toxic metal, affects living systems at different organismal levels, including major storage organs (liver, kidneys), key organs for species survival (gonads), and epigenetic networks regulating gene expression. 5-methylcytosine (5mC) is the most common and best-characterized epigenetic mark among different modified nucleosides in DNA. This important player in methylation-driven gene expression is impacted by cadmium in sentinel terrestrial vertebrates. However, limited information exists regarding its impact on macroinvertebrates, especially land snails commonly used as (eco)toxicological models. We first investigate the methylomic effects of dietary cadmium given as cadmium nitrate on terrestrial mollusks. Mature specimens of the common brown garden snail, , were continuously exposed for four weeks to environmentally-relevant cadmium levels. We determined global genomic DNA methylation in hepatopancreas and ovotestis, as well as changes in the methylation status of CG pairs at the 5' region close to the transcription site of gene encoding the Cd-selective metallothionein (Cd-MT). Weight gain/loss, hypometabolism tendency, and survival rates were also assessed. Although this exposure event did not adversely affect survival, gastropods exposed to the highest Cd dose revealed a significant reduction in body weight and a significant increase in hypometabolic behavior. The hepatopancreas, but not the ovotestis, displayed significant hypermethylation, but only for the aforementioned specimens. We also found that the 5' end of the gene was unmethylated in both organs and its methylation status was insensitive to cadmium exposure. Our results are important since they provide scientists, for the first time, with quantitative data on DNA methylation in gastropod ovotestis and refine our understanding of Cd epigenetic effects on terrestrial mollusks.
Topics: Animals; Cadmium; DNA Methylation; Hepatopancreas; Cadmium Compounds
PubMed: 37073276
DOI: 10.7717/peerj.15032 -
Biology of Reproduction Jun 2023Sea urchins are usually gonochoristic, with all of their five gonads either testes or ovaries. Here, we report an unusual case of hermaphroditism in the purple sea...
Sea urchins are usually gonochoristic, with all of their five gonads either testes or ovaries. Here, we report an unusual case of hermaphroditism in the purple sea urchin, Strongylocentrotus purpuratus. The hermaphrodite is self-fertile, and one of the gonads is an ovotestis; it is largely an ovary with a small segment containing fully mature sperm. Molecular analysis demonstrated that each gonad producedviable gametes, and we identified for the first time a somatic sex-specific marker in this phylum: Doublesex and mab-3 related transcription factor 1 (DMRT1). This finding also enabled us to analyze the somatic tissues of the hermaphrodite, and we found that the oral tissues (including gut) were out of register with the aboral tissues (including tube feet) enabling a genetic lineage analysis. Results from this study support a genetic basis of sex determination in sea urchins, the viability of hermaphroditism, and distinguish gonad determination from somatic tissue organization in the adult.
Topics: Animals; Female; Adult; Male; Humans; Strongylocentrotus purpuratus; Semen; Sea Urchins; Gonads; Disorders of Sex Development
PubMed: 36943312
DOI: 10.1093/biolre/ioad036 -
Experimental Parasitology May 2023Schistosomiasis is a snail-born, neglected tropical disease (NTD) caused by blood flukes (trematode worms) of the genusSchistosoma. It is the second most...
Schistosomiasis is a snail-born, neglected tropical disease (NTD) caused by blood flukes (trematode worms) of the genusSchistosoma. It is the second most socioeconomically devastating parasitic disease after malaria. Urogenital schistosomiasis is caused by Schistosoma haematobium which is transmitted by snail intermediate host of the genus Bulinus. This genus is a model system for the study of polyploidy in animals. This study aims to investigate ploidy levels existing among the Bulinus species and their compatibility with S. haematobium. The specimens were collected from two governorates in Egypt. Chromosomal preparation was made from gonad tissue (ovotestis). This study found two ploidy levels (tetraploid, n = 36 and hexaploid, n = 54) of B. truncatus/tropicus complex in Egypt. Tetraploid B. truncatus was found in El-Beheira governorate while-unexpectedly and for the first time in Egypt, the hexaploid population was found in Giza governorate. This identification focused on shell morphology, chromosomal count, and spermatozoa of each species. Afterward, all species were exposed to S. haematobium miracidia where B. hexaploidus snails were the only refractory species. The histopathological study showed early destruction and abnormal development of S. haematobium in B. hexaploidus tissues. In addition, the hematological investigation showed increasing in the total hemocyte count, the formation of vacuoles, several pseudopodia, and more dense granules in the hemocytes of infected B. hexaploidus snails. In conclusion, there were two types of snails one was refractory and the other was susceptible.
Topics: Male; Animals; Bulinus; Schistosoma haematobium; Tetraploidy; Schistosomiasis haematobia; Disease Vectors
PubMed: 36914064
DOI: 10.1016/j.exppara.2023.108502 -
Biased precursor ingression underlies the center-to-pole pattern of male sex determination in mouse.Development (Cambridge, England) Mar 2023During mammalian development, gonadal sex determination results from the commitment of bipotential supporting cells to Sertoli or granulosa cell fates. Typically, this...
During mammalian development, gonadal sex determination results from the commitment of bipotential supporting cells to Sertoli or granulosa cell fates. Typically, this decision is coordinated across the gonad to ensure commitment to a single organ fate. When unified commitment fails in an XY mouse, an ovotestis forms in which supporting cells in the center of the gonad typically develop as Sertoli cells, while supporting cells in the poles develop as granulosa cells. This central bias for Sertoli cell fate was thought to result from the initial expression of the drivers of Sertoli cell fate, SRY and/or SOX9, in the central domain, followed by paracrine expansion to the poles. However, we show here that the earliest cells expressing SRY and SOX9 are widely distributed across the gonad. In addition, Sertoli cell fate does not spread among supporting cells through paracrine relay. Instead, we uncover a center-biased pattern of supporting cell precursor ingression that occurs in both sexes and results in increased supporting cell density in the central domain. Our findings prompt a new model of gonad patterning in which a density-dependent organizing principle dominates Sertoli cell fate stabilization.
Topics: Female; Mice; Male; Animals; Sex Determination Processes; Gonads; Sertoli Cells; Cell Differentiation; Embryonic Development; SOX9 Transcription Factor; Testis; Sex-Determining Region Y Protein; Mammals
PubMed: 36912416
DOI: 10.1242/dev.201060 -
Parasites & Vectors Feb 2023Biomphalaria glabrata is one of the main intermediate hosts of Schistosoma mansoni, the most widespread species of Schistosoma. Our previous studies proved that...
BACKGROUND
Biomphalaria glabrata is one of the main intermediate hosts of Schistosoma mansoni, the most widespread species of Schistosoma. Our previous studies proved that alternative oxidase (AOX), the terminal oxidase in the mitochondrial respiratory chain, widely exists in several species of intermediate host snails of Schistosoma. Meanwhile, inhibition of AOX activity in Oncomelania hupensis snails could dramatically enhance the molluscicidal effect of niclosamide. As a hermaphroditic aquatic mollusc, the high fecundity and population density of B. glabrata increase the difficulty of snail control, which is one of the critical strategies for schistosomiasis elimination. The present study aimed to investigate the possible role of AOX in the development and fecundity of B. glabrata snail, which could be manipulated more manageable than other species of intermediate host snails of Schistosoma.
METHODS
The dynamic expression of the AOX gene was investigated in different developmental stages and tissues of B. glabrata, with morphological change and oviposition behaviour observed from juvenile to adult snails. Furtherly, dsRNA-mediated knockdown of BgAOX mRNA and the AOX protein activity inhibiting was performed to investigate the effect of AOX on the development and oviposition of snails.
RESULTS
The BgAOX gene expression profile is highly related to the development from late juveniles to adults, especially to the reproductive system of snails, with a positive correlation of 0.975 between egg production and BgAOX relative expression in ovotestis of snails. The inhibition of BgAOX at the transcriptional level and AOX activity could efficiently inhibit snail growth. However, the interference at the BgAOX protein activity level led to more severe tissue damage and more significant inhibition of oviposition than at the transcriptional level. This inhibition of growth and oviposition decreased gradually with the increase in the snail size.
CONCLUSIONS
The inhibition of AOX could efficiently disrupt the development and oviposition of B. glabrata snails, and the intervention targeting AOX at the juvenile stage is more effective for snails. This investigation explored the role of AOX in the growth and development of snails. It would benefit snail control in the future by providing a potential target while using molluscicides more efficiently.
Topics: Animals; Female; Biomphalaria; Oviposition; Schistosoma mansoni; Oxidoreductases
PubMed: 36804043
DOI: 10.1186/s13071-022-05642-8 -
Sexual Development : Genetics,... 2022Ovotesticular disorder of sex development (OT-DSD) is a rare condition defined by concomitance of testicular tissue and ovarian tissue (containing follicles) in the same...
INTRODUCTION
Ovotesticular disorder of sex development (OT-DSD) is a rare condition defined by concomitance of testicular tissue and ovarian tissue (containing follicles) in the same individual. In SRY-negative 46,XX OT-DSD, the presence of testicular tissue may be due to variations in NR5A1. Our aims were to search for NR5A1 variants in SRY-negative 46,XX OT-DSD patients and to perform a systematic review on the contribution of NR5A1 variations to 46,XX OT-DSD.
METHODS
Sanger sequencing of NR5A1 was performed in seven SRY-negative 46,XX OT-DSD patients: five simplex cases and two with another sibling with a 46,XX DSD. Systematic review of original studies on NR5A1 sequencing of 46,XX OT-DSD patients was performed according to PRISMA-P guideline. Case reports were selected for analysis of clinical features. Individuals with NR5A1-associated testicular DSD were not included.
RESULTS
Sanger sequencing of NR5A1 did not reveal pathogenic variants among our patients. Our cohort was included in this systematic review with seven other articles, totalizing fifty-six 46,XX OT-DSD patients investigated by Sanger or whole-exome sequencing. From them, three NR5A1 pathogenic variants were identified (5% of the cases). Clinical analysis of these 3 cases and 5 case reports revealed: predominance of ovotestis (13/16 gonads) and bilateral OT-DSD (5/8 cases).
CONCLUSION
The etiology of most 46,XX OT-DSD cases remains elusive, highlighting the importance of a deeper molecular investigation.
Topics: Humans; Male; Disorders of Sex Development; Gonads; Meta-Analysis as Topic; Ovotesticular Disorders of Sex Development; Steroidogenic Factor 1; Testis
PubMed: 36657429
DOI: 10.1159/000526036 -
BMC Women's Health Dec 2022True hermaphroditism is a rare condition. It is defined as the presence of both testicular and ovarian tissues in the same individual. Sex cord tumour with annular... (Review)
Review
BACKGROUND
True hermaphroditism is a rare condition. It is defined as the presence of both testicular and ovarian tissues in the same individual. Sex cord tumour with annular tubules (SCTAT) is a rare stromal tumour of the sex cord that occurs mostly in the ovaries.
CASE PRESENTATION
A 16-year-old girl presented to the gynaecology department with primary amenorrhea. Gynaecological examination revealed an enlarged clitoris that looked like a small penis. The chromosome karyotype was chimaera. The postoperative pathology confirmed true hermaphroditism with SCTAT. The patient underwent hormonal replacement after an operation and had no evidence of recurrence for 6 months.
CONCLUSION
Cases of true hermaphroditism with SCTAT are extremely rare conditions. Surgery and hormonal replacement are important for improving the prognosis of such patients.
Topics: Male; Female; Humans; Adolescent; Ovarian Neoplasms; Ovotesticular Disorders of Sex Development; Sex Cord-Gonadal Stromal Tumors; Prognosis
PubMed: 36575516
DOI: 10.1186/s12905-022-02137-7