scholarly journals Heterozygous deletion of Sox9 in mouse mimics the gonadal sex reversal phenotype associated with campomelic dysplasia in humans

2020 ◽  
Author(s):  
Stefan Bagheri-Fam ◽  
Alexander N Combes ◽  
Cheuk K Ling ◽  
Dagmar Wilhelm
Keyword(s):  
Genetic Background ◽  
Digital Pcr ◽  
Sex Reversal ◽  
Campomelic Dysplasia ◽  
Skeletal Malformation ◽  
Testis Development ◽  
Mixed Genetic Background ◽  
Sex Development ◽  
Differences Of Sex Development ◽  
Human Disorders

Abstract Heterozygous mutations in the human SOX9 gene cause the skeletal malformation syndrome campomelic dysplasia which in 75% of 46,XY individuals is associated with male-to-female sex reversal. While studies in homozygous Sox9 knockout mouse models confirmed that SOX9 is critical for testis development, mice heterozygous for the Sox9-null allele were reported to develop normal testes. This led to the belief that the SOX9 dosage requirement for testis differentiation is different between humans, which often require both alleles, and mice, in which one allele is sufficient. However, in prior studies, gonadal phenotypes in heterozygous Sox9 XY mice were assessed only by either gross morphology, histological staining or analyzed on a mixed genetic background. In this study, we conditionally inactivated Sox9 in somatic cells of developing gonads using the Nr5a1-Cre mouse line on a pure C57BL/6 genetic background. Section and whole-mount immunofluorescence for testicular and ovarian markers showed that XY Sox9 heterozygous gonads developed as ovotestes. Quantitative droplet digital PCR confirmed a 50% reduction of Sox9 mRNA as well as partial sex reversal shown by an upregulation of ovarian genes. Our data show that haploinsufficiency of Sox9 can perturb testis development in mice, suggesting that mice may provide a more accurate model of human disorders/differences of sex development (DSD) than previously thought.

The role of SOX9 in autosomal sex reversal and campomelic dysplasia

1995 ◽  
Vol 350 (1333) ◽  
pp. 271-278 ◽  
Keyword(s):  
Y Chromosome ◽  
Chromosomal Rearrangements ◽  
Sex Reversal ◽  
Chromosome 17 ◽  
Campomelic Dysplasia ◽  
Skeletal Malformation ◽  
Testis Development ◽  
Human Chromosome 17 ◽  
And Control

In eutherian mammals, the Y-chromosome gene SRY is required for induction of testis development. Although the Y chromosome is sex determining, loci located elsewhere in the genome participate in the complex cascade of genetic interactions required to form a testis. Male to female sex reversal (46,XY females) occurs at a high frequency in individuals afflicted with the skeletal malformation syndrome campomelic dysplasia. Chromosomal translocations in individuals with both syndromes had localized an autosomal sex reversal locus ( SRA1 ) and a campomelic dysplasia locus ( CMPD1 ) to the long arm of human chromosome 17. The molecular cloning of a translocation breakpoint in a sex reversed campomelic dysplasia patient revealed its proximity to SOX9 , a gene which is related to SRY . Analysis of SOX9 in patients without chromosomal rearrangements demonstrated single allele mutations in sex reversed campomelic individuals, linking this gene with both bone formation and control of testis development. Identification of SOX9 as SRA1 / CMPD1 and the role of SOX9 mutations in sex reversal and campomelic dysplasia are discussed.

scholarly journals Knockout of the HMG domain of the porcine SRY gene causes sex reversal in gene-edited pigs

2020 ◽  
Vol 118 (2) ◽  
pp. e2008743118
Author(s):  
Stefanie Kurtz ◽  
Andrea Lucas-Hahn ◽  
Brigitte Schlegelberger ◽  
Gudrun Göhring ◽  
Heiner Niemann ◽  
...  
Keyword(s):  
Sex Determination ◽  
Mutational Analysis ◽  
Mammalian Species ◽  
Digital Pcr ◽  
Sex Reversal ◽  
Large Animal Model ◽  
Pcr Analysis ◽  
Large Animal ◽  
Sry Gene ◽  
Sex Development

The sex-determining region on the Y chromosome (SRY) is thought to be the central genetic element of male sex development in mammals. Pathogenic modifications within the SRY gene are associated with a male-to-female sex reversal syndrome in humans and other mammalian species, including rabbits and mice. However, the underlying mechanisms are largely unknown. To understand the biological function of the SRY gene, a site-directed mutational analysis is required to investigate associated phenotypic changes at the molecular, cellular, and morphological level. Here, we successfully generated a knockout of the porcine SRY gene by microinjection of two CRISPR-Cas ribonucleoproteins, targeting the centrally located “high mobility group” (HMG), followed by a frameshift mutation of the downstream SRY sequence. This resulted in the development of genetically male (XY) pigs with complete external and internal female genitalia, which, however, were significantly smaller than in 9-mo-old age-matched control females. Quantitative digital PCR analysis revealed a duplication of the SRY locus in Landrace pigs similar to the known palindromic duplication in Duroc breeds. Our study demonstrates the central role of the HMG domain in the SRY gene in male porcine sex determination. This proof-of-principle study could assist in solving the problem of sex preference in agriculture to improve animal welfare. Moreover, it establishes a large animal model that is more comparable to humans with regard to genetics, physiology, and anatomy, which is pivotal for longitudinal studies to unravel mammalian sex determination and relevant for the development of new interventions for human sex development disorders.

scholarly journals Functional analysis of Mmd2 and related PAQR genes during sex determination in mice

2021 ◽  
Author(s):  
Liang Zhao ◽  
Ella Thomson ◽  
Ee Ting Ng ◽  
Enya Longmuss ◽  
Terje Svingen ◽  
...  
Keyword(s):  
Sex Determination ◽  
Cell Lineage ◽  
Gonadal Development ◽  
Extensive Study ◽  
Mouse Strains ◽  
Loss Of Function ◽  
Expression Screening ◽  
Testis Development ◽  
Sex Development ◽  
Differences Of Sex Development

Sex determination in eutherian mammals is controlled by the Y-linked gene Sry, which drives the formation of testes in male embryos. Despite extensive study, the genetic steps linking Sry action and male sex determination remain largely unknown. Here, we focused on Mmd2, a gene that encodes a member of the progestin and adipoQ receptor (PAQR) family. We show that Mmd2 is expressed during the sex-determining period in XY but not XX gonads, specifically in the Sertoli cell lineage which orchestrates early testis development. Analysis of knockout mice deficient in Sox9 and Sf1 revealed that Mmd2 operates downstream of these known sex-determining genes. However, when we used CRISPR to ablate Mmd2 in the mouse, fetal testis development appeared to progress normally. To determine if other genes might have compensated for the loss of Mmd2, we identified the closely related PAQR family members Paqr8 and Mmd as also being expressed during testis development. We used CRISPR to generate mouse strains deficient in Paqr8 and Mmd, but both knockout lines appeared phenotypically normal and fertile. Finally, we generated Mmd2;Mmd and Mmd2;Paqr8 double-null embryos and again observed normal testis development. These results may reflect functional redundancy among these factors. Our findings highlight the difficulties involved in identifying genes with a functional role in sex determination and gonadal development through expression screening and loss-of-function analyses of individual candidate genes, and may help to explain the paucity of genes in which variations have been found to cause human disorders/differences of sex development.

scholarly journals Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency

2015 ◽  
Vol 468 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Yi Jin ◽  
Mo Chen ◽  
Trevor M. Penning ◽  
Walter L. Miller
Keyword(s):  
Electron Transfer ◽  
European Ancestry ◽  
Wild Type ◽  
Transient Kinetics ◽  
Skeletal Malformation ◽  
P450 Oxidoreductase ◽  
Sex Development ◽  
Cytochrome P450 Oxidoreductase ◽  
Flavin Binding ◽  
Human Wild Type

We show that the cytochrome P450 oxidoreductase (POR) A287P variant, which can lead to skeletal malformation and disordered sex development, found in 40% of patients of European ancestry is characterized by deficient flavin binding and impaired electron transfer from NADPH.

Recalled and current gender role behavior, gender identity and sexual orientation in adults with Disorders/Differences of Sex Development

2016 ◽  
Vol 86 ◽  
pp. 8-20 ◽  
Author(s):  
Nina Callens ◽  
Maaike Van Kuyk ◽  
Jet H. van Kuppenveld ◽  
Stenvert L.S. Drop ◽  
Peggy T. Cohen-Kettenis ◽  
...  
Keyword(s):  
Sexual Orientation ◽  
Gender Identity ◽  
Gender Role ◽  
Role Behavior ◽  
Sex Development ◽  
Gender Role Behavior ◽  
Differences Of Sex Development

scholarly journals Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development

2018 ◽  
Vol 6 (5) ◽  
pp. 785-795 ◽  
Author(s):  
Patrick Sproll ◽  
Wassim Eid ◽  
Camila R. Gomes ◽  
Berenice B. Mendonca ◽  
Nathalia L. Gomes ◽  
...  
Keyword(s):  
Jigsaw Puzzle ◽  
Sex Development ◽  
Differences Of Sex Development

scholarly journals Transgenic Chickens Overexpressing Aromatase Have High Estrogen Levels but Maintain a Predominantly Male Phenotype

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 83-90 ◽  
Author(s):  
Luke S. Lambeth ◽  
Kirsten R. Morris ◽  
Terry G. Wise ◽  
David M. Cummins ◽  
Terri E. O'Neil ◽  
...  
Keyword(s):  
Small Sample Size ◽  
Sex Differentiation ◽  
Serum Levels ◽  
Sex Reversal ◽  
High Serum ◽  
Small Sample ◽  
Chicken Embryos ◽  
Sex Development ◽  
Multistep Process ◽  
Transgenic Chickens

Abstract Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterized steroidogenic pathway, which is a multistep process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1) is expressed female-specifically from the time of gonadal sex differentiation. Ectopic overexpression of aromatase in male chicken embryos induces gonadal sex reversal, and male embryos treated with estradiol become feminized; however, this is not permanent. To test whether a continuous supply of estrogen in adult chickens could induce stable male to female sex reversal, 2 transgenic male chickens overexpressing aromatase were generated using the Tol2/transposase system. These birds had robust ectopic aromatase expression, which resulted in the production of high serum levels of estradiol. Transgenic males had female-like wattle and comb growth and feathering, but they retained male weights, displayed leg spurs, and developed testes. Despite the small sample size, this data strongly suggests that high levels of circulating estrogen are insufficient to maintain a female gonadal phenotype in adult birds. Previous observations of gynandromorph birds and embryos with mixed sex chimeric gonads have highlighted the role of cell autonomous sex identity in chickens. This might imply that in the study described here, direct genetic effects of the male chromosomes largely prevailed over the hormonal profile of the aromatase transgenic birds. This data therefore support the emerging view of at least partial cell autonomous sex development in birds. However, a larger study will confirm this intriguing observation.

The Interconnected Histories of Endocrinology and Eligibility in Women’s Sport

2018 ◽  
Vol 90 (4) ◽  
pp. 213-220 ◽  
Author(s):  
Alan D. Rogol ◽  
Lindsay Parks Pieper
Keyword(s):  
Female Athletes ◽  
International Association ◽  
Historical Context ◽  
International Olympic Committee ◽  
Elite Sport ◽  
Women's Sport ◽  
Current Effort ◽  
Sex Development ◽  
Differences Of Sex Development

This report illustrates the links between history, sport, endocrinology, and genetics to show the ways in which historical context is key to understanding the current conversations and controversies about who may compete in the female category in elite sport. The International Association of Athletics Federations (IAAF) introduced hyperandrogenemia regulations for women’s competitions in 2011, followed by the International Olympic Committee (IOC) for the 2012 Olympics. The policies concern female athletes who naturally produce higher-than-average levels of testosterone and want to compete in the women’s category. Hyperandrogenemia guidelines are the current effort in a long series of attempts to determine women’s eligibility scientifically. Scientific endeavors to control who may participate as a woman illustrate the impossibility of neatly classifying competitors by sex and discriminate against women with differences of sex development (also called intersex by some).

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