SOX9 Duplication Linked to Intersex in Deer

Kropatsch, Regina; Dekomien, Gabriele; Akkad, Denis A.; Gerding, Wanda M.; Petrasch‐Parwez, Elisabeth; Young, Neil D.; Altmüller, Janine; Nürnberg, Peter; Gasser, Robin B.; Epplen, Jörg T.

doi:10.1371/journal.pone.0073734

Cited by 21 publications

(19 citation statements)

References 27 publications

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“…In fact, duplications of SOX9 are associated with XX sex reversal not only in transgenic mice 9 but also in the recently reported case of a deer, 38 and in three cases of dogs. 39 Our case 3 shows that also interruption of the region upstream to the RevSex can result in XX sex reversal.…”

Section: Discussionmentioning

confidence: 81%

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

et al. 2014

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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

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Section: Discussionmentioning

confidence: 81%

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

et al. 2014

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“…Transgenic mouse studies have shown the crucial roles of Sox9 in testis development: ectopic expression in XX gonads induces testis formation [7] , whilst loss-of-function of the gene causes XY sex reversal, resulting in failure to form Sertoli cells [8] . Gonadal sex reversals caused by misexpression of SOX9 have also been reported in human and European roe deer ( Capreolus capreolus ) [9] , [10] , [11] , and this suggests that the roles of the gene in testis differentiation are widely shared in mammals.…”

Section: Introductionmentioning

confidence: 79%

Mutations in the Testis-Specific Enhancer of SOX9 in the SRY Independent Sex-Determining Mechanism in the Genus Tokudaia

et al. 2014

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SRY (sex-determining region Y) is widely conserved in eutherian mammals as a sex-determining gene located on the Y chromosome. SRY proteins bind to the testis-specific enhancer of SOX9 (TES) with SF1 to upregulate SOX9 expression in undifferentiated gonads of XY embryos of humans and mice. The core region within TES, named TESCO, is an important enhancer for mammalian sex determination. We show that TESCO of the genus Tokudaia lost enhancer activity caused by mutations in its SRY and SF1 binding sites. Two species of Tokudaia do not have the Y chromosome or SRY, and one species has multiple SRYs located on the neo-Y chromosome consisting of the Y fused with an autosome. The sequence of Tokudaia TESCO exhibited more than 83% identity with mouse TESCO, however, nucleotide substitution(s) were found in two out of three SRY binding sites and in five out of six SF1 binding sites. TESCO of all species showed low enhancer activity in cells co-transfected with SRY and SF1, and SOX9 and SF1 in reporter gene assays. Mutated TESCO, in which nucleotide substitutions found in SRY and SF1 binding sites were replaced with mouse sequence, recovered the activity. Furthermore, SRYs of the SRY-positive species could not activate the mutated TESCO or mouse TESCO, suggesting that SRYs lost function as a sex-determining gene any more. Our results indicate that the SRY dependent sex-determining mechanism was lost in a common ancestor of the genus Tokudaia caused by nucleotide substitutions in SRY and SF1 binding sites after emergence of a new sex-determining gene. We present the first evidence for an intermediate stage of the switchover from SRY to a new sex-determining gene in the evolution of mammalian sex-determining mechanism.

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“…A duplication adding a third copy could increase this basal expression level above the threshold needed for testis induction. Interestingly, a duplication of the entire SOX9 region including its regulatory domain was able to trigger XX female-to-male sex reversal in human, deer and dog 4 32 33. Benko and co-workers suggest the involvement of epigenetic packaging of the 78 kb RevSex region, which includes the XXSR, in the regulation of SOX9 expression 12.…”

Section: Discussionmentioning

confidence: 99%

Copy number variation of two separate regulatory regions upstream ofSOX9causes isolated 46,XY or 46,XX disorder of sex development

et al. 2015

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SOX9 Duplication Linked to Intersex in Deer

Cited by 21 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

Mutations in the Testis-Specific Enhancer of SOX9 in the SRY Independent Sex-Determining Mechanism in the Genus Tokudaia

Copy number variation of two separate regulatory regions upstream ofSOX9causes isolated 46,XY or 46,XX disorder of sex development

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