XX male sex reversal with genital abnormalities associated with a de novo <i>SOX3</i> gene duplication

Moalem, Sharon; Babul‐Hirji, Riyana; Stavropolous, Dmitri J.; Wherrett, Diane K.; Bägli, Darius; Thomas, Paul Q.; Chitayat, David

doi:10.1002/ajmg.a.35390

Cited by 77 publications

(52 citation statements)

References 27 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16 Interestingly, SOX3 duplications have been reported in two unrelated 46,XY individuals with X-linked hypopituitarism, whereas their carrier mothers were unaffected. 36,37 No hypopituitarism was present in our case 20 or in the patient reported by Moalem et al 17 An X-linked dominant but leaky mutation affecting sex development in a portion of XX subjects might be hypothesized, either as a consequence of the X-inactivation pattern in the developing gonad or of specific genomic modifiers.…”

Section: Sox3 Duplicationsupporting

confidence: 42%

“…35 Duplications involving SOX3 and deletions of its 5′ region (Figure 1d) have been reported in at least four cases of XX DSD. 16,17 Moreover, a mouse model in which SOX3 is ectopically expressed in the developing gonads shows complete XX sex reversal, suggesting that gain-of-function mutations of SOX3 might act as an SRY surrogate in sex determination, promoting SOX9 gonadal expression. 16 Interestingly, SOX3 duplications have been reported in two unrelated 46,XY individuals with X-linked hypopituitarism, whereas their carrier mothers were unaffected.…”

Section: Sox3 Duplicationmentioning

confidence: 99%

“…16 Moreover, duplications of SOX3 or its 5′ region have been reported in 46,XX DSD patients. 16,17 Here, we present two new subjects with cryptic duplications upstream of SOX9 that were identified among 19 unrelated novel cases with 46,XX isolated DSDs, either familial (2 cases) or sporadic (17 cases), all SRY-negative. In the same cohort, we also identified the second case of reciprocal translocation upstream of SOX9, causing XX DSD.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

View full text Add to dashboard Cite

Duplications in the~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our 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. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects. European Journal of Human Genetics (2015) 23, 1025-1032; doi:10.1038/ejhg.2014.237; published online 5 November 2014 INTRODUCTION 46,XX disorders of sex development (DSDs) are congenital conditions in which, in the presence of a female karyotype, the development of gonadal and anatomical sex is atypical, ranging from various degrees of ambiguous genitalia to phenotypic males with azoospermia. These conditions are poorly characterized, at least in subjects whose DNA does not contain SRY, the gene triggering testis differentiation in mammals. 1 In fact, in most XX males, SRY is transposed to the tip of Xp as a consequence of a recurrent Xp;Yp translocation, arising predominantly by nonallelic homologous recombination between PRKX and PRKY on a particular Y haplotypic background. 2,3 These males, usually with small testes, are essentially picked up among men with nonobstructive azoospermia.A much less well-understood category is that of the 46,XX DSDs negative for SRY. Recently, six of these cases have been reported

show abstract

Section: Sox3 Duplicationsupporting

confidence: 42%

Section: Sox3 Duplicationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

View full text Add to dashboard Cite

show abstract

“…This hypothesis has been strongly supported by recent studies of Sox3 transgenic mice and human sex reversal cases. Ectopic expression of Sox3 in the urogenital ridge of transgenic mice induces complete XX male sex reversal 8 , and rearrangements in the Sox3 regulatory region are associated with XX male sex reversal in human 8,41 , suggesting that Sry and Sox3 are functionally interchangeable in sex determination. Thus, although loss of Sox3 function does not affect sex determination 42 , certain gain-of-function mutations in Sox3 may result in XX male sex reversal in mouse and human by mimicking the function of Sry, supporting the notion that Sry .…”

Section: Discussionmentioning

confidence: 99%

Co-option of Sox3 as the male-determining factor on the Y chromosome in the fish Oryzias dancena

et al. 2014

View full text Add to dashboard Cite

Sex chromosomes harbour a primary sex-determining signal that triggers sexual development of the organism. However, diverse sex chromosome systems have been evolved in vertebrates. Here we use positional cloning to identify the sex-determining locus of a medaka-related fish, Oryzias dancena, and find that the locus on the Y chromosome contains a cis-regulatory element that upregulates neighbouring Sox3 expression in developing gonad. Sex-reversed phenotypes in Sox3 Y transgenic fish, and Sox3 Y loss-of-function mutants all point to its critical role in sex determination. Furthermore, we demonstrate that Sox3 initiates testicular differentiation by upregulating expression of downstream Gsdf, which is highly conserved in fish sex differentiation pathways. Our results not only provide strong evidence for the independent recruitment of Sox3 to male determination in distantly related vertebrates, but also provide direct evidence that a novel sex determination pathway has evolved through co-option of a transcriptional regulator potentially interacted with a conserved downstream component.

show abstract

“…vious studies have identified various heterozygous duplications involving SOX3 and/or its flanking regions in patients with 46,XX disorders of sex development (DSD) [Sutton et al, 2011;Moalem et al, 2012;Mizuno et al, 2014]. These duplications were predicted to induce ectopic expression of SOX3 in 46,XX gonads, which switches the developmental process toward testicular formation [Sutton et al, 2011].…”

mentioning

confidence: 99%

SOX3 Overdosage Permits Normal Sex Development in Females with Random X Inactivation

Igarashi

Mikami

Katsumi

et al. 2015

Sex Dev

View full text Add to dashboard Cite

Submicroscopic duplications involving SOX3 and/or its flanking regions have been identified in 46,XX individuals both with and without disorders of sex development, raising the question whether SOX3 overdosage is sufficient to induce testicular development in genetically female individuals. Here, we report a mother-daughter pair with female phenotypes and random X inactivation. The individuals carry complex X chromosomal rearrangements leading to a copy number gain of genomic regions involving SOX3 and its upstream region. The amplified DNA fragments were detected at Xq27. These results provide evidence that SOX3 overdosage permits normal sex development in 46,XX individuals with random X inactivation.

show abstract

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

Cited by 77 publications

References 27 publications

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

Co-option of Sox3 as the male-determining factor on the Y chromosome in the fish Oryzias dancena

SOX3 Overdosage Permits Normal Sex Development in Females with Random X Inactivation

Contact Info

Product

Resources

About