ESPE Yearbook of Paediatric Endocrinology

Mol Genet Genomic Med. 2018 Sep;6(5):785–795.

doi: 10.1002/mgg3.445. PubMed PMID: 29998616

Chromobox protein homolog 2 (CBX2) has two isoforms, CBX2.1 and the shorter CBX2.2. CBX2.1 was previously shown to be essential for male gonadal development, when a mutation was identified in a girl with 46,XY DSD. CBX2.1 stimulates male-specific genes (SF1 and SOX9) and inhibits female-specific factors (FOXL2). However, the function of CBX2.2 was unknown.

This study describes two patients with 46,XY DSD, perineal hypospadias, no palpable gonads and compound heterozygous mutations in CBX2.2. Possible binding targets of CBX2.2 were identified using DNA adenine methyltransferase identification (DamID). The functional effects of the mutations were explored using quantitative real-time PCR. The authors found that both CBX2.2 mutations failed to regulate the expression of EMX2, HOXA13, and MAK, suggesting that failed regulation of these targets might contribute to the pathophysiology.

The authors suggest that the most relevant CBX2.2 target for sex development seems to be EMX2, since deletions have been reported to cause 46,XY DSD ranging from hypospadias to gonadal dysgenesis. In human development, EMX2 and CBX2 are simultaneously expressed in the gonadal anlage at 7 weeks of gestation, i.e. prior to SRY, suggesting a role in the formation of the early gonad. Other targets of interest were MAK, male germ cell associated kinase, involved in cell cycle regulation, and HOXA13, for which mutations lead to the hand-foot-genital syndrome, Müllerian duct fusion defects in females and hypospadias in males.

In conclusion, the CBX2.2 mutations failed to regulate the expression of genes essential for sex development resulting in 46,XY DSD. This study demonstrates the complexity of the regulation of sex determination and development that we are just beginning to understand. CBX2 adds an important piece to the picture.