Gonadal mosaicism mediated female-biased gender control in mice.
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ABSTRACT:
SUBMITTER: Bai M
PROVIDER: S-EPMC9237195 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We report a family with four girls with moderate to severe intellectual disability and epilepsy. Two girls showed regression in adolescence and died of presumed sudden unexpected death in epilepsy at 16 and 22 years. Whole exome sequencing identified a truncating pathogenic variant in IQSEC2 at NM_001111125.2: c.2679_2680insA, p.(D894fs*10), a recently identified cause of epileptic encephalopathy in females (MIM 300522). The IQSEC2 variant was identified in both surviving affected sisters but in neither parent. We describe the phenotypic spectrum associated with IQSEC2 variants, highlighting how IQSEC2 is adding to a growing list of X-linked genes that have a female-specific phenotype typically associated with de novo mutations. This report illustrates the need for careful review of all whole exome data, incorporating all possible modes of inheritance including that suggested by the family history.
| S-EPMC5477359 | biostudies-literature
Project description:BackgroundHemophilia A (HA) and B (HB) are X-linked recessive disorders that mainly affect males born from a mother carrier. Females are rarely affected but a number of mechanisms have been suggested in symptomatic females, such as skewed X-chromosome inactivation (XCI), chromosomal rearrangements, and hermaphrodites. Different methodologies are required to elucidate the underlying causes of such diseases in female patients.MethodsThree families with female hemophilia patients, including two HA and one HB, were enrolled for genetic analyses. Cytogenetics, molecular examinations on F8 and F9 genes, XCI assay, and linkage analysis were performed.ResultsAll three female patients are demonstrated to be heterozygous for an F8, or F9 mutation: one patient is inherited from her unaffected mother and the other two are sporadic cases. All three patients exhibit skewed XCI. The inherited patient is found to be unmethylated in the maternal X chromosome, which increases the potential for the expression of the mutant allele. The two sporadic cases are hypomethylated or unmethylated in the paternal X chromosome, suggesting that paternal gonadal mosaicism may exist in these families.ConclusionsIn addition to screening for coagulation function, different genetic analyses are mandatory to explore the nature of mechanisms responsible for the X-linked recessive disorders in female patients as shown in this study. Our results confirm that skewed XCI is responsible for hemophilia in heterozygous female patients. Likewise, our results implicate that parental gonadal mosaicism, followed by skewed XCI, contributes to hemophilia in "sporadic" female patients.
| S-EPMC9600608 | biostudies-literature
Project description:AbstractNociplastic pain conditions develop predominantly in women. We recently established a murine nociplastic pain model by applying postinjury thermal (40°C) stimulation to an injured (capsaicin-injected) area, triggering a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. The nociplastic pain state was centrally maintained by spinal microglia in males but peripherally by ongoing afferent activity at the previously injured area in females. Here, we investigated whether gonadal hormones are critical for the development of this peripherally maintained nociplastic pain state in females. Although the transition to a nociplastic pain state still occurred in ovariectomized females, the pain state was maintained neither by ongoing afferent activity at the previously injured area nor by spinal microglia. Estradiol reconstitution a week before the injury plus postinjury stimulation, but not after the transition had already occurred, restored the development of peripherally maintained nociplastic mechanical hypersensitivity in ovariectomized females. G protein-coupled estrogen receptor antagonism during the transition phase mimicked ovariectomy in gonad-intact females, whereas the receptor antagonism after the transition gradually alleviated the nociplastic mechanical hypersensitivity. At the previously injured area, afferents responsive to allyl isothiocyanate (AITC), a TRPA1 agonist, contributed to the maintenance of nociplastic mechanical hypersensitivity in gonad-intact females. In ex vivo skin-nerve preparations, only AITC-responsive afferents from the nociplastic pain model in gonad-intact females showed ongoing activities greater than control. These results suggest that gonadal hormones are critical for peripherally maintained nociplastic pain state in females by sensitizing AITC-responsive afferents to be persistently active.
| S-EPMC9755459 | biostudies-literature
Project description:BackgroundGNAO1 encodes an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins). Mutations in GNAO1 result in two clinical phenotypes: Early infantile epileptic encephalopathy 17 (EEIE17-OMIM #615473) and Neurodevelopmental disorder with involuntary movements (NEDIM-OMIM #617493). Both are inherited as autosomal dominant disorders and originate mainly as de novo. Only a few are reported as gonadal mosaicism.Materials and methodsWe recruited and retrospectively reviewed five patients from two families seen at King Faisal Specialist Hospital and Research Centre in Riyadh (KFSHRC).ResultsAll patients presented with severe neurodevelopmental disorder, followed by progressive dystonia and hyperkinetic movements. In addition, none of the patients had seizures which was consistent with NEDIM phenotype. The specific diagnosis was not clinically entertained and was only found on whole exome sequencing (WES), which identified two variants (c.724-8G > A & c.709G > A). Both variants were previously reported as pathogenic de novo in patients with NEDIM, and one was reported as parental gonadal mosaicism.ConclusionWe report these variants as additional variants in GNAO1 gene that may be inherited as parental gonadal mosaicism. Both variants resulted in NEDIM with no observed clinical differences in the severity than the reported cases. This noticeable reported association between GNAO1 gene associated disorders and gonadal mosaicism should be considered in reproductive genetic counselling of affected families. Furthermore, in view of these reports, more studies with prospective data collection to explore the association between GNAO1 and gonadal mosaicism and the underlying mechanisms will be necessary.
| S-EPMC9248221 | biostudies-literature
Project description:Gender- and sex- related differences represent a new frontier towards patient-tailored medicine, taking into account that theoretically every medical specialty can be influenced by both of them. Sex hormones define the differences between males and females, and the different endocrine environment promoted by estrogens, progesterone, testosterone, and their precursors might influence both human physiology and pathophysiology. With the term Gender we refer, instead, to behaviors, roles, expectations, and activities carried out by the individual in society. In other words, "gender" refers to a sociocultural sphere of the individual, whereas "sex" only defines the biological sex. In the last decade, increasing attention has been paid to understand the influence that gender can have on both the human physiology and pathogenesis of diseases. Even the clinical response to therapy may be influenced by sex hormones and gender, but further research is needed to investigate and clarify how they can affect the human pathophysiology. The path to a tailored medicine in which every patient is able to receive early diagnosis, risk assessments, and optimal treatments cannot exclude the importance of gender. In this review, we have focused our attention on the involvement of sex hormones and gender on different endocrine diseases.
| S-EPMC6215564 | biostudies-other
Project description:Individuals born on the spectrum of genetic abnormalities known as mixed gonadal dysgenesis (MGD) have a wide range of anatomical findings and management can be challenging in the newborn and adolescent. Historically, many individuals with MGD have undergone gonadectomy to avert the risk of gonadal malignancy. However, gonadectomy deprives patients of the benefits of their endogenous hormones, potential fertility, and in the case with MGD, has historically been done prior to addressing gender identity. Some patient advocates have proposed a delayed approach to surgical reconstructions and/or gonadectomy in other differences/disorders of sex development (DSD), particularly in patients with congenital adrenal hyperplasia and androgen insensitivity syndrome. In many areas of the world, there continues to be a shift toward delayed reconstructions and hesitancy regarding irreversible gonadectomy. To date, no clinical management protocol addressing these issues from a patient-centered approach has been described. We review what is known about malignancy risk and propose a management protocol for those with MGD that involves shared decision making regarding the gonads and addresses the long-term challenges with regard to gender and anatomy.
| S-EPMC6922540 | biostudies-literature
Project description:The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.
| S-EPMC5448135 | biostudies-literature
Project description:Research suggests that women, but not men, manifest gender-biased expectations of altruism: while women expect other women to be more altruistic, men expect women to be as generous as men. Do adolescents expect women and men to behave differently regarding altruism? I analyse adolescents' gender beliefs about altruism using a modified Dictator Game. Results indicate that adolescents believe that others of same gender are more altruistic than others of the opposite gender. I also found that adolescents' agreement with the existence of different societal roles for men and women moderates the relationship between gender and gender beliefs. Although it was expected that adolescents who agree with different gender roles would expect women to be more generous, surprisingly, the results presented here confirm this only for male adolescents, but in the opposite direction: the more male adolescents agree with the existence of different gender roles, the more they seem to believe that men are more generous than women. Meanwhile, female adolescents believe that women are more altruistic unconditionally. Thus, the previously documented bias seems to be already in place during adolescence, above and beyond other confounding factors. Adolescents' in-group bias, and their socialization into different cultural values regarding gender roles are discussed as potential explanatory mechanisms for these gender beliefs.
| S-EPMC5902534 | biostudies-literature
Project description:Males and females often display extensive phenotypic differences, and many of these sexual dimorphisms are thought to result from differences between males and females in expression of genes present in both sexes. Sex-biased genes have been shown to exhibit accelerated rates of evolution in a wide array of species, however the cause of this remains enigmatic. In this study, we investigate the extent and evolutionary dynamics of sex-biased gene expression in zebrafish. Our results indicate that both male-biased genes and female-biased genes exhibit accelerated evolution at the protein level. In order to differentiate between adaptive and nonadaptive causes, we tested for codon usage bias and signatures of different selective regimes in our sequence data. Our results show that both male- and female-biased genes show signatures consistent with adaptive evolution. In order to test the generality of our findings across fish, we also analyzed publicly available data on sticklebacks, and found results consistent with our findings in zebrafish.
| S-EPMC5203780 | biostudies-literature
Project description:We analyzed liver gene expression from male and female ARE-Del mice, which have prolonged and chronic expression of IFN gamma through deletion of the IFN gamma 3’ UTR AU-rich element.
2016-04-29 | GSE76309 | GEO