XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication

  title={XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication},
  author={Sharon Moalem and Riyana Babul‐Hirji and Dmitri J. Stavropolous and Diane K. Wherrett and Darius J. B{\"a}gli and Paul Q Thomas and David Chitayat},
  journal={American Journal of Medical Genetics Part A},
Differentiation of the bipotential gonad into testis is initiated by the Y chromosome‐linked gene SRY (Sex‐determining Region Y) through upregulation of its autosomal direct target gene SOX9 (Sry‐related HMG box‐containing gene 9). Sequence and chromosome homology studies have shown that SRY most probably evolved from SOX3, which in humans is located at Xq27.1. Mutations causing SOX3 loss‐of‐function do not affect the sex determination in mice or humans. However, transgenic mouse studies have… 
Interchromosomal insertional translocation at Xq26.3 alters SOX3 expression in an individual with XX male sex reversal.
This is the first demonstration of altered SoX3 expression in an individual with XX male sex reversal and suggests that SOX3 can substitute for SRY to initiate male development in humans.
Human sex-determination and disorders of sex-development (DSD).
Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD)
Three phenotypically normal patients presenting with azoospermia and 46,XX testicular DSD are identified and a duplication refines the minimal region associated with 46, XX‐SRY negative DSD to a 40.7–41.9  kb element located ∼600 kb upstream of SOX9.
Copy number variation in the region harboring SOX9 gene in dogs with testicular/ovotesticular disorder of sex development (78,XX; SRY-negative)
Two highly polymorphic copy number variable regions (CNVRs) upstream of SOX9 and CNVR2 encompassing CanRevSex were identified and it was observed that the average number of copies in CNVR1 was higher in XX DSD than in control animals.
Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3
Collectively in this cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for ~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father.
Co-option of Sox3 as the male-determining factor on the Y chromosome in the fish Oryzias dancena.
This work uses positional cloning to identify the sex-determining locus of a medaka-related fish, Oryzias dancena, and finds that the locus on the Y chromosome contains a cis-regulatory element that upregulates neighbouring Sox3 expression in developing gonad.
A Korean boy with 46,XX testicular disorder of sex development caused by SOX9 duplication
Although SRY-negative 46,XX testicular DSD is a rare condition, an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management.
Disorders of Sex Determination
A 33-year-old patient who had a small testicular size, hypergonadotropic hypogonadism, and nonobstructive azoospermia is presented, focusing on the approaches to diagnosis and the lessons learned and review shortly the genetics of human sex determination.
46,XX Male Disorder of Sexual Development: A Case Report
An adolescent who presented with low testicular volume and who was diagnosed as a 46,XX male was reported, and SRY positivity was demonstrated in the patient by fluorescence in situ hybridization method.
Methylation Patterns of SOX3, SOX9, and WNT4 Genes in Gonads of Dogs with XX (SRY-Negative) Disorder of Sexual Development
The SOX3 promoter showed significantly higher methylation in the ovotesticular XX DSD cases and the testicular XXDSD and control males, suggesting that SOX 3 methylation may play a role in canine XX D SD pathogenesis.


Identification of SOX3 as an XX male sex reversal gene in mice and humans.
SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
XY sex reversal associated with a nonsense mutation in SRY.
Sox3 Is Required for Gonadal Function, but Not Sex Determination, in Males and Females
It is concluded that Sox3 is not required for gonadal determination but is important for normal oocyte development and male testis differentiation and gametogenesis and targeted mutagenesis to delete Sox3 from mice.
Delayed Sry and Sox9 expression in developing mouse gonads underlies B6-Y(DOM) sex reversal.
Stabilization of beta-catenin in XY gonads causes male-to-female sex-reversal.
Results show that activation of beta-catenin in otherwise normal XY mice effectively disrupts the male program and results in male-to-female sex-reversal, and will further the understanding of the mechanisms controlling sex determination and the molecular mechanisms that lead to sex- reversal.
XX males SRY negative: a confirmed cause of infertility
The results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region.
Sex reversal caused by Mus musculus domesticus Y chromosomes linked to variant expression of the testis-determining gene Sry.
Using a semiquantitative RT-PCR assay, it is shown that representatives of the three Y(DOM) classes have variant Sry expression patterns, that severity of sex reversal correlates with Sry mRNA titers, and that genetic correction of the sex reversal results in the upregulation of Sryexpression.
Genetic mechanisms underlying male sex determination in mammals
  • R. Piprek
  • Biology
    Journal of Applied Genetics
  • 2010
In the absence of Sry, the predomination of the female pathway results in the realization of a robust genetic program that drives ovarian differentiation.
SOX3 is an X-linked gene related to SRY.
The phenotype of the patient and the expression of SOX3 gene in neuronal tissues raises the possibility that this gene is a candidate gene for Borjeson-Forssman-Lehmann, an X-linked mental retardation syndrome.
Sox3 functions in a cell-autonomous manner to regulate spermatogonial differentiation in mice.
The results indicate that Sox3 functions in an intrinsic manner to promote differentiation of spermatogonia in prepubertal mice but it is not required for ongoing sperMatogenesis in adults.