ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Sci Rep. 2019, Nov 12; 9: 16552. doi: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851130/pdf/41598_2019_Article_53006.pdf

A complex network of genes contributes to (human) sex development. Among these, CBX2 is involved in the initial programming of the bipotential gonad to either the ovary or testis pathway. Chromosomal male mice lacking M33 (the homolog of human CBX2 ) show complete sex reversal with additional developmental anomalies in skeleton, spleen, adrenals and kidneys, and are infertile (1). Similarly, Biason-Lauber reported a 46,XY girl with a double heterozygous variant in CBX2.1 resulting in male-to-female sex reversal with ovary-like gonads (2).

To further explore the role of CBX2 in human sex development, her group now performed genome wide protein-DNA interaction (Dam-ID) studies in combination with transcriptome studies in a Sertoli cell model after knockdown/-out and overexpression of CBX2.1. Using an unbiased bioinformatic approach to look for CBX2.1 interacting genes and proteins, they identified novel and known targets of sex determination, differentiation and fertility. Overall, CBX2.1 seems to be a stimulator of the male gonadal pathway and an inhibitor of the female pathway.

This work nicely illustrates how next generation sequencing approaches and bioinformatic tools can help in elucidating the role of novel gene variants identified in DSD individuals; in addition, hidden interacting partners may be uncovered. Using such approaches, the complex puzzle of sex development may be solved step-by-step and genotype-phenotype correlations may be elucidated.

References:

1. Cbx2, a Polycomb Group Gene, Is Required for Sry Gene Expression in Mice. Yuko Katoh-Fukui ¹, Kanako Miyabayashi, Tomoko Komatsu, Akiko Owaki, Takashi Baba, Yuichi Shima, Tomohide Kidokoro, Yoshiakira Kanai, Andreas Schedl, Dagmar Wilhelm, Peter Koopman, Yasushi Okuno, Ken-ichirou Morohashi. Endocrinology 2012 Feb;153(2):913–24. PMID: 22186409. DOI: 10.1210/en.2011-1055.2. Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene. Biason-Lauber A, Konrad D, Meyer M, DeBeaufort C, Schoenle EJ. Am J Hum Genet. 2009 May;84(5):658–63. doi: 10.1016/j.ajhg.2009.03.016. Epub 2009 Apr 9. PMID: 19361780.