Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development
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Citações na Scopus
16
Tipo de produção
article
Data de publicação
2018
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY
Autores
SPROLL, Patrick
EID, Wassim
GOMES, Camila R.
BIASON-LAUBER, Anna
Citação
MOLECULAR GENETICS & GENOMIC MEDICINE, v.6, n.5, p.785-795, 2018
Resumo
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, invitro 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.
Palavras-chave
CBX2, DamID, DSD, EMX2, gonad development
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