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\"What makes you the way you are--and what makes each of us different from everyone else? In Innate, leading neuroscientist and popular science blogger Kevin Mitchell traces human diversity and individual differences to their deepest level: in the wiring of our brains. Deftly guiding us through important new research, including his own work, he explains how variations in the way our brains develop before birth strongly influence our psychology and behavior throughout our lives, shaping our personality, intelligence, sexuality, and even the way we perceive the world. We all share a genetic program for making a human brain, and the program for making a brain like yours is specifically encoded in your DNA. But, as Mitchell explains, the way that program plays out is affected by random processes of development that manifest uniquely in each person, even identical twins. The key insight of Innate is that the combination of these developmental and genetic variations creates innate differences in how our brains are wired--differences that impact all aspects of our psychology--and this insight promises to transform the way we see the interplay of nature and nurture. Innate also explores the genetic and neural underpinnings of disorders such as autism, schizophrenia, and epilepsy, and how our understanding of these conditions is being revolutionized. In addition, the book examines the social and ethical implications of these ideas and of new technologies that may soon offer the means to predict or manipulate human traits are\"-- Provided by the publisher.

JDP2 and ATF3 belong to the family of AP-1 protein. JDP2, a transcription factor, can bind to AP-1 site as well as cAMP responsive element (CRE) site in numerous cis-elements of the target genes. JDP2 has been shown to be involved in cancer development and cell-cycle regulation. Previously, we had shown that JDP2 activates Mc2r transcriptional activity. Since ATF3 and JDP2 share high similarity in C-terminal domains with identities of 65% and ATF3 can bind to p53 and regulate p53 transcriptional activity and stability, we hypothesized that JDP2 may have ability to regulate p53 and MDM2 (the main regulator of p53). Herein, we demonstrate for the first time the relationship between JDP2 and MDM2. First, we found that JDP2 can directly bind to MDM2. Secondly, though ATF3 dose-dependently increases MDM2 level, JDP2 dose-dependently decreases MDM2 level. Moreover, the C-terminus of JDP2 is required for regulation of MDM2 level. Finally, using p53RE-Luc (14X) for p53 transactivation study, while MDM2 decreases p53 transactivation, JDP2 dose-dependently abolishes MDM2-mediated p53 repression. Taken together, our results demonstrate that JDP2 directly binds to MDM2 and reduces MDM2-mediated p53 repression, suggesting that JDP2 is a novel regulator of MDM2. Since p53-MDM2 pathway is an important regulator in endocrinology and reproduction, our finding provides a new layer of regulatory mechanism for fertility, tumor suppression, and longevity. Presentation: No date and time listed

Specialized cell lineages within the anterior pituitary produce specific hormones which, in turn, regulate diverse biological processes ranging from growth, metabolism, and reproduction to stress. Interestingly, these specialized cell lineages exhibit a high degree of cellular plasticity, readily altering their differentiation state to produce different hormones in response to organismal demand. Underlying molecular mechanisms controlling cellular plasticity in the pituitary are not fully defined but appear to involve post-transcriptional regulation exerted by the Musashi family of sequence-specific RNA binding proteins. Musashi is a bifunctional regulator of target mRNAs and can exert either repression or activation of translation in a context-dependent manner. Our recent work has implicated a role for Musashi-dependent repression of key pituitary mRNAs in the mouse, including a lineage-specific transcription factor (Pou1f1), the gonadotropin releasing hormone receptor (Gnrhr), and two anterior pituitary hormones (Prl and Tshb). In this study, we look to determine the potential relevance of Musashi-dependent mRNA translational control to the human pituitary. Reflecting our findings in the adult mouse, a re-analysis of published human fetal pituitary single cell RNA sequencing data revealed Musashi1 (MSI1) and Musashi2 (MSI2) expression in both stem/progenitor cell populations as well as in all hormone-producing cell lineages of the anterior pituitary. We further report that the human homologs of identified Musashi-target mRNAs in the mouse pituitary also possess Musashi binding elements (MBEs) in their 3' untranslated regions (UTRs). In the case of the human Pou1f1 3' UTR, we were able to verify Musashi-dependent mRNA translational repression in reporter assays as seen with the murine Pou1f1 3' UTR. Interestingly, a germline Pou1f1 mutation identified in human patients, disrupts a consensus MBE in the human Pou1f1 3' UTR and abolishes Musashi-dependent repression. We developed a bioinformatic pipeline to characterize pathogenic human mutations catalogued in the Geno2MP database for disruption or creation of consensus MBEs in pituitary-specific mRNA 3' UTRs. Our findings suggest an evolutionarily conserved role for Musashi in the post-transcriptional regulation of pituitary mRNAs in both mice and humans and identify several human mutations which may perturb Musashi regulation of human pituitary function. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor–associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90–related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.

Introduction An intact GH-IGF-1 axis is known to be essential for proper growth. However, cases in which individuals with growth hormone deficiency (GHD) reach target height without the use of GH suggest that other mechanisms may play a role in the growth process. Out of 209 patients with hypopituitarism followed in the endocrinology clinic at HCFMUSP, 9 presented with normal stature despite GHD and hypogonadotropic hypogonadism. Among them, 1 male patient presented with tall stature. The mechanisms under growth without growth hormone are poorly understood, so we hypothesized that genetic mutations in genes related to tall stature could be a plausible explanation. The aim of the present work was to look for allelic variants in the exome that could be associated with tall stature, combined pituitary hormone deficiency and/or skeletal deformities. The index male patient presented at the age of 28 to a medical assistance due to the lack of pubertal development, leading to the diagnosis of FSH/LH and TSH deficiencies and thus treated accordingly. He was still growing even under testosterone replacement and noticed that his hand and fingers also got bigger in this period. At 32-year-old he presented to our service with a stature of 193.5cm (z score of +2.40) being out of his target height range. An arm span of 195cm was notice together with skeletal deformities such as claw toes, trigger fingers in hands and a barrel chest. At this time ACTH and GH deficiencies were diagnosed and an adult dose of GH was initiated. Over one year treatment he grew 1 cm even presenting complete closed epiphyses in hands but incomplete epiphyseal fusion in the iliac crest (Risser 4). In the skeletal X ray scoliosis, deformities in hands and feet were noticed. Pituitary MRI revealed an ectopic neurohypophysis and a reduced adenohypophysis. Whole exome sequencing was performed and allelic variants in exonic or splice site regions with frequency of less than 1% were prioritized. Out of 26 variants, 13 were classified as VUS or pathogenic in the genes PSG4, ZGPAT, LRP2, LRP5, LRP6, RYR1, REL SPAST, SDHC, EGFR, ARID3B and TGFB2, being the last 5 genes never described in 4 different populational databases (gnomAD, 1000G, ABraOM and SELAdb). Allelic variant in TGFB2 gene has been related to Marfan syndrome. Family members are having these genes in the process of being segregated. Conclusion Mutations in genes related to tall stature may be a mechanism that could explains normal growth among individuals with GHD. Presentation: Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The transforming growth factor beta (TGFβ) signaling pathway has critical roles in the transduction of paracrine and autocrine signals that control development, reproduction, and cancer. To study the tissue-specific contribution of TGFβ signaling in the endometrium, we developed mice with conditional deletion SMAD2 and SMAD3 in the endometrial epithelium (using Lactoferrin-cre, \"Ltf-cre\"). We identified that double conditional deletion of SMAD2 and SMAD3 in the endometrial epithelium resulted in endometrial hyperplasia by 12-weeks of age, with myometrial invasion, metastasis, and death by 6-9-months of age. Smad2/3-Ltf-cre mice also lost epithelial progesterone receptor expression in the endometrium by 12 weeks of age. To study the signaling mechanism that controlled the malignant transformation of the glandular epithelium in Smad2/3-Ltf-cre mice, we developed 3-dimensional (3D) endometrial organoid cultures from the uterine epithelial tissues of control and mutant mice. To test how suppression of TGFβ signaling affected endometrial regeneration, 3D endometrial organoids from WT or Smad2/3-Ltf-cre mice were grown in the presence or absence of the TGFβ receptor inhibitor, A83-01. Using these conditions, we identified that WT endometrial organoids cultured with the SB505124 inhibitor or from Smad2/3-Ltf-cre mice, developed abnormal morphology. Histological analysis of the endometrial organoids showed that organoids cultured with A83-01 or from Smad2/3-Ltf-cre mice, developed increased secretory-like cells with increased mucin-1 expression. RNA-sequencing of the endometrial organoids revealed that a large number of differentially expressed genes were conserved between the WT organoids cultured with A83-01 and those from Smad2/3-Ltf-cre mice. Gene ontology analysis of the differentially expressed genes indicated that pharmacological or genetic inhibition of TGFβ signaling, resulted in over-representation of gene families related to BMP/SMAD1/5 signaling and retinoic acid signaling, with decreased enrichment of WNT/β-catenin signaling. These studies indicate that TGFβ-mediated signals are critical to endometrial function and that perturbation of this balance results in endometrial cancer. Funding support NICHD grants R00-HD096057 (to DM) and R01-HD032067 (to MMM), and grants NGP10125 and 1016187 from the Burroughs Wellcome Fund (to DM). Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.

Background Prader-Willi syndrome (PWS) is a complex rare genetic disorder associated with hypothalamic dysfunction, pituitary hormone deficiencies, hyperphagia and (morbid) obesity. PWS is caused by loss of expression of paternally expressed genes on chromosome 15q11.2-q13. The most common genetic mechanisms leading to PWS are paternal deletion (DEL) and maternal uniparental disomy (mUPD). DELs can be subdivided in type 1 and (smaller) type 2 deletions (DEL-1, DEL-2). Most research has focused on behavioral, cognitive and psychological differences between patients with a DEL-1, DEL-2 or mUPD. However, little is known about the genetic subtype differences in relation to physical health problems. Methods We reviewed the medical files of all adults with genetically confirmed PWS who visited the outpatient clinic of the Center for Adults with Complex Rare Genetic Syndromes at the Erasmus University Medical Center, Rotterdam, the Netherlands, between January 2015 and June 2021. All patients underwent a systematic health screening, including a structured interview, a medical questionnaire, a complete physical examination, biochemical measurements, and a review of the medical records. Health problems, physical complaints, symptoms of disease and behavioral challenges were compared between adults with an mUPD and DEL and between adults with a DEL-1 and DEL-2. Results Twenty-eight adults had an mUPD and 65 a DEL (13 DEL-1, 27 DEL-2, 25 unspecified). Gender, age and BMI did not differ between the genetic subgroups. Although psychiatric problems (psychotic episodes) were significantly more often present in adults with an mUPD (P < 0.001) and scoliosis was more prevalent among patients with DEL (P = 0.04), there was only a slight difference in prevalence of other medical problems like hypertension, cold intolerance, edema, hyperphagia, skin picking, abdominal pain and fatigue. There were no significant differences between DEL-1 and DEL-2. However, fatigue, cold intolerance, edema and hyperphagia were slightly more prevalent among adults with a DEL-1, whereas osteopenia, constipation and skin picking were more prevalent among adults with a DEL-2. Conclusion The differences in health problems between PWS adults with DEL-1, DEL-2 and mUPD are mostly present in the psychological domain. Especially psychotic episodes were more frequent in adults with an mUPD. Apart from scoliosis, there were no significant differences in physical health outcomes between the genetic subtypes. Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Introduction The pituitary gland controls several mechanisms as metabolism, growth, and reproduction, in response to hypothalamic stimuli. The adequate temporal/ spatial expression of transcription factors is mandatory for a normal pituitary development. PROP1 transcription factor is widely known as a key pituitary regulator. Pathogenic variants in the PROP1 gene are the main familial causes of hypopituitarism accounting for about 54% of the cases. Aim To characterize the expression of genes involved in pituitary cells determination and specification during pituitary high demand period such as sexual maturation compared to adulthood in the Ames mice. Methods Weight and naso-anal length were measured. Pituitary glands were collected from 5 wild type (WT) and 5 prop1 mutant (Mut) animals with 30 (P30), 40, (P40), and 60 (P60) days after birth. RT-qPCR was performed to analyze the pituitary transcription factors Sox2, Sox3, Hesx1, Otx2, and genes codifying the hormones GH, TSH, LH/ FSH, CGA, and PRL by SYBR® Green (QIAGEN, Valencia, CA). They were normalized by endogenous genes and performed in triplicate. The target genes relative quantification was performed using the mutant related to its age paired wild type as a calibrator and the results were expressed as fold change. Immunofluorescence of SOX2 (ab97959, Abcam, UK) (1: 1600) and pituitary hormones GH, LH, and FSH (1: 250) were done in pituitaries at P60 and its aged paired control, stained with propidium iodide (1: 1000) for nucleus and the secondary antibody Alexa FluorÒ488 (ab150077, Abcam, UK) (1: 1000). Results All mutant mice presented decreased weight and naso-anal length at the three analyzed periods. The expression of the pituitary stem/ progenitor cell marker Sox2 was increased at P30 and P60 and decreased at P40. Sox3 was increased at P30 and decreased at P40 and P60. Hesx1 was increased at P30 and P60 and decreased at P40. Otx2 was increased at all periods. At P30 the genes codifying pituitary hormones was decreased, except for Tsh and Fsh. At P40 it was observed increased expression of the genes codifying Gh, Lh, Fsh and Prl, while Tsh and Cga expression was reduced. At P60 all pituitary hormones codifying genes presented decreased expression. The immunofluorescence at P60 showed increased expression of SOX2, similar expression of FSH, and decreased expression of GH and LH related to their age paired WT. Conclusion Despite the absence of PROP1, Hesx1 is downregulated at P40. Pituitary cell subtype differentiation and hormonal production is observed at transcriptional and protein levels, showing that pituitary cells can differentiate and produce hormones in the absence of Prop1. The recovery of pituitary capacity to differentiate in mutant suggests the involvement of another factor in the pituitary cell differentiation pathway that could compensate the lack of Prop1. Presentation: Saturday, June 11, 2022 11:30 a.m. - 11:45 a.m.

Introduction Male infertility can be categorized as endocrine and systemic disorders, primary testicular defects in spermatogenesis, sperm transport disorders and idiopathic male infertility. Chromosomal abnormalities are one of the primary testicular defects. The overall incidence of chromosome abnormalities in infertile men is estimated to be around 5.8%. XX male is a rare sex chromosomal disorder in infertile men. We present case of a young patient with infertility, azoospermia, hypergonadotropic hypogonadism and classical (46, XX) karyotype with negative FISH and SRY gene. Case report: 28-Year-old gentleman was referred to adult endocrinology clinic as part of work up for infertility. Initial work up included 2 semen analyses which were consistent with azoospermia. Examination revealed height 180 cm, weight 77 kg, a body mass index 24 kg/m2, normal phenotypic male without gynecomastia and had normal male pattern hair distribution. Genital examination showed normal male phallus without hypospadias, a hypoplastic scrotum, bilateral firm testes, with no varicocele or hydrocele. Labs were suggestive of compensated primary hypogonadism (FSH 47.9 mIU/ml, LH 20.4 mIU/ml, total testosterone 397.9 ng/dl by LC/MS, free testosterone 15.76 ng/dl by equilibrium dialysis, Inhibin B < 10 pg/ml, and anti-Mullerian hormone 0.390 ng/ml. Given normal testosterone levels, he was not started on testosterone replacement. Karyotype analysis revealed 46 XX and FISH was negative for SRY gene. CT imaging of abdomen and pelvis did not reveal any Mullerian structures, prostrate and seminal vesicles reported as normal. Patient met with a Urologist and was informed that testicular sperm extraction will not be a possibility for him. Patient had a detailed consultation with a geneticist for genetic and family counseling. Chromosome microarray analysis was obtained and was normal. Invitae Disorders of sex development (DSD) panel obtained for genetic sequencing of 53 genes including SOX-9, DHH, WNT4, WT1, was found to be non-diagnostic. Conclusion and Discussion SRY negative 46 XX male is a DSD and a rare genetic cause of male factor infertility, with a discrepancy between genotype and phenotypic sex. In the case presented, genetic work up for potential etiologies has been unrevealing. Further studies are needed to identify the genetic causes of the SRY negative 46 XX male phenotype. Physicians involved in care of these patients should orient with clinical management and prognosis. For Classical 46 XX Males seeking fertility, the current options include invitro-fertilization with donor sperm or adoption only. Testosterone replacement should be considered to correct hypogonadism for physical and sexual well-being. Genetic consultation should be sought in all these cases. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.