Sox9 Duplications Are a Relevant Cause of Sry-Negative XX Sex Reversal Dogs

Rossi, Elena; Radi, Orietta; Lorenzi, L. De; Vetro, Annalisa; Groppetti, D.; Bigliardi, Enrico; Luvoni, G.C.; Rota, Ada; Camerino, Giovanna; Zuffardi, Orsetta; Parma, P.

doi:10.1371/journal.pone.0101244

Cited by 44 publications

(59 citation statements)

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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. Altogether our data reinforce the role of the desert region upstream of SOX9 in the regulation of this gene, as indicated by an altered histone methylation signature demonstrated in one of the RevSex duplicated cases.…”

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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“…Noteworthy, most of these cases have been described before the discovery of the SRY gene, and thus, we cannot exclude that some of them were SRY-positive. In 2012, 29 new cases of SRY -negative XX male dogs were described in an exhaustive review [Meyers-Wallen et al, 2012], followed by 7 other reports of XX dogs with testicular or ovotesticular DSD [Groppetti et al, 2012;Max et al, 2012;Del Carro et al, 2014;Rossi et al, 2014;MarcinkowskaSwojak et al, 2015;Pérez-Gutiérrez et al, 2015;Salamon et al, 2015]. Notably, many investigations have been conducted on a large American Cocker Spaniel pedigree .…”

Section: Sex Reversal In Dogsmentioning

confidence: 99%

“…The occurrence of a Robertsonian translocation involving CFA5 and CFA23 in an XX sexreversed dog [Switonski et al, 2011] suggested that another genetic factor responsible for this phenotype was located on CFA23, as this chromosome carries 3 important genes involved in sex determination (FOXL2 , PISRT1, and CTNNB1) . More recently it has been shown that a duplication covering the whole SOX9 open reading frame as well as a large part of the 5 ′ region was responsible for XX sex reversal in dogs [Rossi et al, 2014[Rossi et al, , 2015. Duplication of SOX9 is thus the only causative mutation for XX sex reversal in dogs identified so far, but it is certainly not the only one as many other cases do not carry this duplication [Marcinkowska-Swojak et al, 2015;Szczerbal et al, 2016].…”

Section: Sex Reversal In Dogsmentioning

confidence: 99%

“…If true, the combination of these different mutations could also explain the huge phenotypic variability of this trait. SOX9 GoF mutations have already been shown to be responsible for XX sex reversal in dogs and humans [Rossi et al, 2014]. In humans, the duplication of a 42-kb region named RevSex and located ∼ 600 kb upstream of SOX9 has been involved in XX sex reversal [Hyon et al, 2015].…”

Section: Sex Reversal In Pigsmentioning

confidence: 99%

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Sex Reversal in Non-Human Placental Mammals

Parma

Veyrunes

Pailhoux

2016

Sex Dev

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Gonads are very peculiar organs given their bipotential competence. Indeed, early differentiating genital ridges evolve into either of 2 very distinct organs: the testis or the ovary. Accumulating evidence now demonstrates that both genetic pathways must repress the other in order for the organs to differentiate properly, meaning that if this repression is disrupted or attenuated, the other pathway may completely or partially be expressed, leading to disorders of sex development. Among these disorders are the cases of XY male-to-female and XX female-to-male sex reversals as well as true hermaphrodites, in which there is a discrepancy between the chromosomal and gonadal sex. Here, we review known cases of XY and XX sex reversals described in mammals, focusing mostly on domestic animals where sex reversal pathologies occur and on wild species in which deviations from the usual XX/XY system have been documented.

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“…Among monogenic DSD, the most frequent cases involve the presence of testes or ovotestes (despite the absence of the SRY gene) in individuals with a female karyotype (78,XX) and lack of the SRY gene . The molecular background of this developmental defect has not been fully elucidated yet, but it is expected to be related to duplications or multiplications in the region harbouring the SOX9 gene (Rossi et al 2014;Marcinkowska-Swojak et al 2015). The only doi: 10.17221/8884-VETMED monogenic DSD with a defined molecular background is the persistent Müllerian duct syndrome -PMDS (Wu et al 2009).…”

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confidence: 99%