Sexual Development最新文献

{"title":"WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease.","authors":"Maria T M Ferrari,&nbsp;Andreia Watanabe,&nbsp;Thatiane E da Silva,&nbsp;Nathalia L Gomes,&nbsp;Rafael L Batista,&nbsp;Mirian Y Nishi,&nbsp;Leila C P de Paula,&nbsp;Eduardo C Costa,&nbsp;Elaine M F Costa,&nbsp;Priscilla Cukier,&nbsp;Luiz F Onuchic,&nbsp;Berenice B Mendonca,&nbsp;Sorahia Domenice","doi":"10.1159/000517373","DOIUrl":"https://doi.org/10.1159/000517373","url":null,"abstract":"<p><p>Wilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 1","pages":"46-54"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39322489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome.","authors":"Anil Kumar,&nbsp;Rajni Sharma,&nbsp;Mohammed Faruq,&nbsp;Manoj Kumar,&nbsp;Shilpa Sharma,&nbsp;Ralf Werner,&nbsp;Olaf Hiort,&nbsp;Jain Vandana","doi":"10.1159/000519047","DOIUrl":"https://doi.org/10.1159/000519047","url":null,"abstract":"<p><p>This study describes the clinical, biochemical, and molecular characteristics of Indian children with 46,XY DSD and suspected androgen insensitivity syndrome (AIS). Fifty children (median age 3.0 years, range 0-16.5 years) with 46,XY DSD and a suspected diagnosis of AIS were enrolled. Sanger sequencing was performed to identify pathogenic variants in the androgen receptor (AR) gene and to study genotype-phenotype correlations. All 5 (100%) patients with CAIS and 14/45 (31%) patients with PAIS had pathogenic/likely pathogenic variants in the AR gene (overall, 14 different variants in 19 patients; 38.8%). There was no significant difference in clinical (cryptorchidism, hypospadias, or external masculinizing score) or biochemical parameters (gonadotropins and testosterone) between patients with or without pathogenic variants. However, patients with AIS were more likely to have a positive family history, be assigned female gender at birth, and present with gynaecomastia at puberty. Three novel pathogenic/likely pathogenic variants, including one splice donor site variant c.2318+1G>A, one frameshift variant p.H790Lfs*40, and one missense variant p.G821E, were identified in 3 patients with CAIS. The missense variant p.G821E was predicted as deleterious, damaging, disease-causing, and likely functionally inactive by in silico analysis and protein modelling study. Two previously not reported pathogenic/likely pathogenic variants, including p.R386H and p.G396R, were identified in patients with PAIS. This study contributes in expanding the spectrum of pathogenic variants in the AR gene in patients with AIS. Only 31% patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene, suggesting other possible mechanisms or candidate genes may be responsible for such a phenotypic presentation.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 1","pages":"34-45"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39550738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Germ Cells Determine Their Own Sexual Fate in Mice.","authors":"Yumiko Saga","doi":"10.1159/000520976","DOIUrl":"https://doi.org/10.1159/000520976","url":null,"abstract":"<p><strong>Background: </strong>Whether to produce sperm or eggs is the most basic and important choice from the perspective of germ cell development and differentiation. However, the induction mechanism has not received much attention until relatively recently. This is because the issue of sexual differentiation has generally been considered a theme of somatic cells to make a testis or ovary. Basically, the sex of individual somatic cells and germ cells matches. Therefore, the sex of germ cells is thought to follow the sex of somatic cells once determined. However, researchers realized that a big, open question remained: What somatic cell signals actually induce the sexual differentiation of germ cells and what is the sex determinant in germ cells?</p><p><strong>Summary: </strong>In vitro experiments demonstrated that 2 somatic signals (BMP and RA) act directly on germ cells to induce oogonia. Therefore, these 2 signals may be referred to as oogonia inducers. From the viewpoint of germ cells, an independent experiment identified SMAD4 and STRA8, which are directly downstream of BMP and RA, respectively, acting in germ cells as female determinants. However, what about male? If these factors are female determinants, their absence may result in the induction of spermatogonia. This may be true in vivo because germ cells enter a male pathway if they do not receive these signals even in the ovary. However, this has not been confirmed in an in vitro culture system. There should be signals required for germ cells to enter a male pathway.</p><p><strong>Key messages: </strong>The important message is that although testis-specific factors secreted from the testis are considered to include male-inducing factors for germ cells, this may not be the case, and the male-inducing factor, if it exists, also exists in the ovary.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 5-6","pages":"329-341"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9781573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex Determination in Nematode Germ Cells.","authors":"Ronald E Ellis","doi":"10.1159/000520872","DOIUrl":"https://doi.org/10.1159/000520872","url":null,"abstract":"<p><strong>Background: </strong>Animal germ cells differentiate as sperm or as oocytes. These sexual fates are controlled by complex regulatory pathways to ensure that the proper gametes are made at the appropriate times.</p><p><strong>Summary: </strong>Nematodes like Caenorhabditis elegans and its close relatives are ideal models for studying how this regulation works, because the XX animals are self-fertile hermaphrodites that produce both sperm and oocytes. In these worms, germ cells use the same signal transduction pathway that functions in somatic cells. This pathway determines the activity of the transcription factor TRA-1, a Gli protein that can repress male genes. However, the pathway is extensively modified in germ cells, largely by the action of translational regulators like the PUF proteins. Many of these modifications play critical roles in allowing the XX hermaphrodites to make sperm in an otherwise female body. Finally, TRA-1 cooperates with chromatin regulators in the germ line to control the activity of fog-1 and fog-3, which are essential for spermatogenesis. FOG-1 and FOG-3 work together to determine germ cell fates by blocking the translation of oogenic transcripts.</p><p><strong>Key messages: </strong>Although there is great diversity in how germ cell fates are controlled in other animals, many of the key nematode genes are conserved, and the critical role of translational regulators may be universal.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 5-6","pages":"305-322"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378769/pdf/nihms-1756851.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum.","authors":"","doi":"10.1159/000525934","DOIUrl":"10.1159/000525934","url":null,"abstract":"","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 4","pages":"295-298"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10695332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the X and Y Chromosomes in the Female Germ Cell Line Development in the Mouse (Mus musculus).","authors":"Wataru Yamazaki,&nbsp;Seang Lin Tan,&nbsp;Teruko Taketo","doi":"10.1159/000521151","DOIUrl":"https://doi.org/10.1159/000521151","url":null,"abstract":"<p><strong>Background: </strong>In eutherian mammals, the sex chromosome complement, XX and XY, determines sexual differentiation of gonadal primordia into testes and ovaries, which in turn direct differentiation of germ cells into haploid sperm and oocytes, respectively. When gonadal sex is reversed, however, the germ cell sex becomes discordant with the chromosomal sex. XY females in humans are infertile, while XY females in the mouse (Mus musculus) are subfertile or infertile dependent on the cause of sex reversal and the genetic background. This article reviews publications to understand how the sex chromosome complement affects the fertility of XY oocytes by comparing with XX and monosomy X (XO) oocytes.</p><p><strong>Summary: </strong>The results highlight 2 folds disadvantage of XY oocytes over XX oocytes: (1) the X and Y chromosomes fail to pair during the meiotic prophase I, resulting in sex chromosome aneuploidy at the first meiotic division and (2) expression of the Y-linked genes during oocyte growth affects the transcriptome landscape and renders the ooplasmic component incompetent for embryonic development.</p><p><strong>Key message: </strong>The XX chromosome complement gives the oocyte the highest competence for embryonic development.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 5-6","pages":"355-364"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9839465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis.","authors":"David Zarkower,&nbsp;Mark W Murphy","doi":"10.1159/000518272","DOIUrl":"https://doi.org/10.1159/000518272","url":null,"abstract":"<p><p>Transcriptional regulators related to the invertebrate sexual regulators doublesex and mab-3 occur throughout metazoans and control sex in most animal groups. Seven of these DMRT genes are found in mammals, and mouse genetics has shown that one, Dmrt1, plays a crucial role in testis differentiation, both in germ cells and somatic cells. Deletions and, more recently, point mutations affecting human DMRT1 have demonstrated that its heterozygosity is associated with 46,XY complete gonadal dysgenesis. Most of our detailed knowledge of DMRT1 function in the testis, the focus of this review, derives from mouse studies, which have revealed that DMRT1 is essential for male somatic and germ cell differentiation and maintenance of male somatic cell fate after differentiation. Moreover, ectopic DMRT1 can reprogram differentiated female granulosa cells into male Sertoli-like cells. The ability of DMRT1 to control sexual cell fate likely derives from at least 3 properties. First, DMRT1 functionally collaborates with another key male sex regulator, SOX9, and possibly other proteins to maintain and reprogram sexual cell fate. Second, and related, DMRT1 appears to function as a pioneer transcription factor, binding \"closed\" inaccessible chromatin and promoting its opening to allow binding by other regulators including SOX9. Third, DMRT1 binds DNA by a highly unusual form of interaction and can bind with different stoichiometries.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 2-3","pages":"112-125"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8885888/pdf/nihms-1726204.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10461733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Nationwide Study of the Prevalence and Initial Management of Atypical Genitalia in the Newborn in Scotland.","authors":"Martina E Rodie,&nbsp;Salma R Ali,&nbsp;Arundathi Jayasena,&nbsp;Naser R Alenazi,&nbsp;Martin McMillan,&nbsp;Kathryn Cox,&nbsp;Sumaiya M Cassim,&nbsp;Stuart Henderson,&nbsp;Ruth McGowan,&nbsp;S Faisal Ahmed","doi":"10.1159/000517327","DOIUrl":"https://doi.org/10.1159/000517327","url":null,"abstract":"<p><p>Provision of optimum healthcare for infants with atypical genitalia requires a clear understanding of the occurrence of this condition. The objective of this study was to determine the prevalence of atypical genitalia and its initial management. A prospective, electronic survey of clinicians within managed clinical networks in Scotland was undertaken between 2013 and 2019. Notification from clinicians was sought for term neonates requiring specialist input for atypical genitalia. Additional information was also sought from the 4 regional genetics laboratories that provided details for neonates who had an urgent karyotype performed for atypical genitalia or sex determination. In total, the study identified 171 term infants who required some investigation for atypical genitalia in the neonatal period, providing a birth prevalence of 1:1,881 term births. Of the 171 infants, 97 (57%) had specialist input over the first 3 months of life, providing a birth prevalence of 1:3,318 term births that received specialist input for atypical genitalia. A total of 92 of these 97 cases had complete 3-month follow-up data, 62 (67%) presented within 24 h of birth, and age at presentation ranged from birth to 28 days. Age at sex assignment ranged from birth to 14 days, and in 63 cases (68%), sex assignment occurred at birth. Thus, the birth prevalence of a case of atypical genitalia where sex assignment was reported to be delayed beyond birth was estimated at 1:11,097 births. In 1 case sex was re-assigned at 3 months. Atypical genitalia requiring specialist input within the first month of life are rare in term newborns, and in only a third of these cases, sex assignment is delayed beyond birth. This study provides new clinical benchmarks for comparing and improving the delivery of care in centres that manage these conditions.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 1","pages":"11-18"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000517327","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39281044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"9th International Symposium in Disorders/Differences of Sex Development.","authors":"","doi":"10.1159/000525564","DOIUrl":"10.1159/000525564","url":null,"abstract":"<p><p>See separate collated abstract file.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 1","pages":"1-91"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43837491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are NR5A1 Variations a Frequent Cause of 46,XX Ovotesticular Disorders of Sex Development? Analysis from a Single Center and Systematic Review.","authors":"Beatriz Amstalden Barros,&nbsp;Mara Sanches Guaragna,&nbsp;Helena Fabbri-Scallet,&nbsp;Maricilda Palandi de Mello,&nbsp;Gil Guerra-Júnior,&nbsp;Andréa Trevas Maciel-Guerra","doi":"10.1159/000526036","DOIUrl":"https://doi.org/10.1159/000526036","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>The etiology of most 46,XX OT-DSD cases remains elusive, highlighting the importance of a deeper molecular investigation.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"16 4","pages":"242-251"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10311803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}