ESPE Abstracts (2015) 84 FC6.4

Severe 46,XY Disorder of Sex Development due to CBX2 Isoform 2 Mutation is Distinct from CBX2.1 Deficiency and is Likely due to EMX2 Dysregulation in the Human Developing Gonad

Wassim Eida, Elaine Costab, Patrick Sprolla & Anna Lauber-Biasona


aUniversity of Fribourg, Fribourg, Switzerland; bUniversity of São Paulo Medical School, São Paulo, Brazil


Background: The process of sexual differentiation is central for reproduction of almost all metazoan. Recently, we identified CBX2.1 a chromatin architecture regulator, as an essential transactivator for human male gonadal development. CBX2 has a second isoform CBX2.2. Since nothing is known about the role of CBX2.2 in human sex development, we took advantage of the p.C132R mutation in CBX2.2 in a 46,XY disorder of sex development (DSD) patient with complete female phenotype and dysgenetic gonads.

Objective and hypotheses: To place CBX2.2 in the sex development cascade and gain insights in DSD mechanism of disease.

Method: We used the DNA adenine methyltransferase identification and next-generation sequencing in the human testicular NT2-D1 cells. The validation was carried out by overexpression of either WT or mutated CBX2.2 and qRT-PCR of the candidates.

Results: We identified 1901 CBX2.2 targets. We then selected a subset of six candidates unique targets of CBX2.2. for validation based on potential links to sex development (Pathway Studio 10.5): EMX2, MAK, HOXA13, WDR77, TWIST1, and BNC2. The most relevant for us is EMX2: Emx2 XY deficient mice have gonadal agenesis and patients with deletions encompassing EMX2 have 46,XY DSD. EMX2 and CBX2 are expressed at 7 weeks of gestation in humans, suggesting a role in the formation of the early gonad. WT CBX2.2 increased the expression of EMX2 (3.2×) whereas the mutated CBX2.2 protein was inactive, indicating that the effect is CBX2.2-specific. Thus, it is intriguing to hypothesise that a mutation in CBX2.2 impairing EMX2 expression causes gonadal dysgenesis in 46,XY individuals similarly to EMX2 haploinsufficiency but distinct from 46,XY CBX2.1 deficient patients, whose gonads presented with apparent ovarian tissue.

Conclusion: Taken together, using a novel approach we were able to identify targets of CBX2.2 in the human sex development cascade, which could help to gain insights in the biology of the process and help elucidate the molecular basis of DSD.

Funding: This work was supported by Grant of the Swiss National Science Foundation (number 320030_130645).

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