Abstract
BackgroundOne of the defining moments of human life occurs early during embryonic development, when individuals sexually differentiate into either male or female. Perturbation of this process can lead to disorders/differences of sex development (DSD). Chromobox protein homolog 2 (CBX2) has two distinct isoforms, CBX2.1 and CBX2.2: the role of CBX2.1 in DSD has been previously established, yet to date the function of the smaller isoform CBX2.2 remains unknown.MethodsThe genomic DNA of two 46,XY DSD patients was analysed using whole exome sequencing. Furthermore, protein/DNA interaction studies were performed using DNA adenine methyltransferase identification (DamID) to identify putative binding partners of CBX2. Finally, in vitro functional studies were used to elucidate the effect of wild‐type and variant CBX2.2 on selected downstream targets.ResultsHere, we describe two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads, each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT). We show that both CBX2.2 variants fail to regulate the expression of genes essential for sexual development, leading to a severe 46,XY DSD defect, likely because of a defective expression of EMX2 in the developing gonad.ConclusionOur study indicates a distinct function of the shorter form of CBX2 and by identifying several of its unique targets, can advance our understanding of DSD pathogenesis and ultimately DSD diagnosis and management.
Highlights
Disorder of sex development (DSD) combines a broad spectrum of different phenotypes, defined as congenital conditions in which the development of the gonad and/or anatomical sex is atypical
One of the genes implicated in differences of sex development (DSD) is Chromobox protein homolog 2 (CBX2)/M33, a member of the Polycomb group (PcG) proteins, that are conserved regulatory factors initially discovered in Drosophila, best known for
From a more mechanistic point of view, we demonstrated that CBX2.1 might have a role as transactivator, distinct from its known function as chromatin‐modifier (Biason‐ Lauber, Konrad, Meyer, DeBeaufort, & Schoenle, 2009)
Summary
Disorder of sex development (DSD) combines a broad spectrum of different phenotypes, defined as congenital conditions in which the development of the gonad and/or. One of the genes implicated in DSD is CBX2/M33, a member of the Polycomb group (PcG) proteins, that are conserved regulatory factors initially discovered in Drosophila, best known for. Functional studies demonstrated that the CBX2.1 variant does not properly bind to and does not adequately regulate the expression of target genes essential for sex development such as SF1/ NR5A1. We investigated the c.394T>C (p.Cys132Arg) and the c.460delT (p.Cys154fs) CBX2.2 variants, from two individuals with 46, XY DSD, characterized by atypical external genitalia and dysgenetic testis
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