Severe sex differentiation disorder in a boy with a 3.8 Mb 10q25.3–q26.12 microdeletion encompassing <i>EMX2</i>

Piard, Juliette; Mignot, Brigitte; Arbez-Gindre, Francine; Aubert, D.; Morel, Yves; Rozé, Virginie; McElreavy, Kenneth; Jonveaux, Philippe; Valduga, Mylène; Maldergem, Lionel Van

doi:10.1002/ajmg.a.36662

Cited by 27 publications

(25 citation statements)

References 18 publications

(21 reference statements)

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“…Emx2 expression is stimulated by Wnt and Bmp signalling in nervous system development (Theil, Aydin, Koch, Grotewold, & Ruther, ) and it is repressed by HOXA10 during development of the endometrium of mice and humans (Daftary & Taylor, ; Troy, Daftary, Bagot, & Taylor, ) but very little is known about the control of EMX2 in the developing gonad. In patients, deletions encompassing EMX2 cause 46,XY DSD ranging from hypospadias to gonadal dysgenesis (Piard et al., ), confirming its role in human gonadal development (MIM 269160). In human development, EMX2 and CBX2 are simultaneously expressed in the gonadal anlage at 7 weeks of gestation, i.e.…”

Section: Discussionmentioning

confidence: 88%

Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development

Sproll

Eid

Gomes

et al. 2018

Molec Gen & Gen Med

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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.

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Section: Discussionmentioning

confidence: 88%

Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development

Sproll

Eid

Gomes

et al. 2018

Molec Gen & Gen Med

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“…( AKR1C2/AKR1C4 ) [Fluck et al, 2011] • ww domain-containing oxidoreductase ( WWOX ) [White et al, 2012] • zinc finger protein, multiple 2 ( ZFPM2 ) or friend of GATA2 ( FOG2 ) [Bashamboo et al, 2014] • empty spiracles, drosophila, 2, homolog of ( EMX2 ) [Piard et al, 2014] • hedgehog acyltransferase ( HHAT ) [Callier et al, 2014] • fibroblast growth factor receptor 2 ( FGFR2 ) [BagheriFam et al, 2015] Next-generation sequencing techniques allow the description of new candidate genes involved in regulating sex development and will also verify the hypothesis of a possible di-or oligenic origin for different sex development in some patients.…”

Section: From Cytogenetic To Molecular Diagnosismentioning

confidence: 99%

Development of Laboratory Investigations in Disorders of Sex Development

Audí

Camats²,

Fernández‐Cancio³

et al. 2017

Sex Dev

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Scientific knowledge to understand the biological basis of sex development was prompted by the observation of variants different from the 2 most frequent body types, and this became one of the fields first studied by modern pediatric endocrinology. The clinical observation was supported by professionals working in different areas of laboratory sciences which led to the description of adrenal and gonadal steroidogenesis, the enzymes involved, and the different deficiencies. Steroid hormone measurements evolved from colorimetry to radioimmunoassay (RIA) and automated immunoassays, although gas and liquid chromatography coupled to mass spectrometry are now the gold standard techniques for steroid measurements. Peptide hormones and growth factors were purified, and their measurement evolved from RIA to automated immunoassays. Hormone action mechanisms were described, and their specific receptors were characterized and assayed in experimental materials and in patient tissues and cell cultures. The discovery of the genetic basis for variant sex developments began with the description of the sex chromosomes. Molecular technology allowed cloning of genes coding for the different proteins involved in sex determination and development. Experimental animal models aided in verifying the roles of proteins and also suggested new genes to be investigated. New candidate genes continue to be described based on experimental models and on next-generation sequencing of patient DNAs.

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“…The kidneys, ureters, gonads, and genital tracts are completely absent in Emx2 À/À mutant mice, whereas the adrenal glands and bladder develop normally. Recently, Piard et al (2014) diagnosed a male patient who presented with 46,XY DSD, a single kidney, intellectual disability, and the smallest microdeletion including EMX2 reported to date. EMX2 haploinsufficiency in human is likely to explain the masculinization defect observed, similar to what has been described in mice.…”

Section: Emx2mentioning

confidence: 99%

“…MAPK signaling in gonad development has been recently demonstrated by the identification of a mutation in Map3k4 in mouse, resulting in XY individuals with male-to-female sex reversal (Piard et al 2014). More importantly, a related MAP3K4 gene, MAP3K1, has been identified in humans as a novel gene causing 46,XY gonadal dysgenesis (Loke et al 2014;Muzio et al 2005).…”

Section: Map Kinasesmentioning

confidence: 99%

The Battle of the Sexes: Human Sex Development and Its Disorders

Biason‐Lauber

2016

Results and Problems in Cell Differentiation

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The process of sexual differentiation is central for reproduction of almost all metazoan and therefore for maintenance of practically all multicellular organisms. In sex development we can distinguish two different processes: First, sex determination is the developmental decision that directs the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development. The second process known as sex differentiation takes place once the sex determination decision has been made through factors produced by the gonads that determine the development of the phenotypic sex. Most of the knowledge on the factors involved in sexual development came from animal models and from studies of cases in whom the genetic or the gonadal sex does not match the phenotypical sex, i.e., patients affected by disorders of sex development (DSD). Generally speaking, factors influencing sex determination are transcriptional regulators, whereas factors important for sex differentiation are secreted hormones and their receptors. This review focuses on the factors involved in gonadal determination, and whenever possible, references on the "prismatic" clinical cases are given.

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Severe sex differentiation disorder in a boy with a 3.8 Mb 10q25.3–q26.12 microdeletion encompassing EMX2

Cited by 27 publications

References 18 publications

Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development

Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development

Development of Laboratory Investigations in Disorders of Sex Development

The Battle of the Sexes: Human Sex Development and Its Disorders

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