ESPEYB18 6. Differences of Sexual Development (DSD) and Gender Dysphoria (GD) Basic and Genetic Research of DSD (6 abstracts)
6.2. Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene
Eozenou C , Gonen N , Touzon MS , Jorgensen A , Yatsenko SA , Fusee L , Kamel AK , Gellen B , Guercio G , Singh P , Witchel S , Berman AJ , Mainpal R , Totonchi M , Mohseni Meybodi A , Askari M , Merel-Chali T , Bignon-Topalovic J , Migale R , Costanzo M , Marino R & Ramirez P & et al.
Proc Natl Acad Sci USA. 2020 Jun 16;117(24):13680–13688. 10.1073/pnas.1921676117. PMID: 32493750.
On the search for a genetic cause for 46,XX virilization due to testicular (TDSD) or ovotesticular DSD (OTDSD), 78 individuals were studied by whole exome sequencing. In 7 cases, heterozygous de novo variants were found in the 4th zinc finger (ZF4) of the Wilms tumor 1 gene (WT1). Modelling of these variants in human granulosa cells and mice recapitulated the phenotype.
While many individuals with a non-syndromic form of OTDSD/TDSD carry the SRY gene, the underlying genetic cause in others remains unsolved. WT1 is a transcription factor with 4 zinc finger motives for DNA binding, which comes in 4 isoforms. It is important for normal development of the urogenital organs, heart and diaphragma. Together with steroidogenic factor 1, WT1 is crucial for mammalian gonadogenesis. So far, haploinsufficiency of WT1 was identified in the WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, retardation), while specific variants were found in autosomal dominant Frasier, Denys-Drash and Meacham syndromes. 46,XY individuals with WT1 variants manifest with ambiguous or female typical external genitalia at birth, while affected 46,XX individuals so far were noted to have either normal ovaries, primary ovarian insufficiency or streak gonads in combination with nephrotic syndrome. For an overview see the OMIM synopsis: https://www.omim.org/clinicalSynopsis/table?mimNumber=194080,136680,608978,156240,256370,194070
The paper by Eozenou et al. now shows that with specific heterozygous variants located in the ZF4 of WT1, yet another phenotype is possible. It is suggested that these variants bind and thereby sequester the essential pro-ovary factor β-cathenin, which promotes testis formation and inhibits ovary development. This illustrates nicely, how genetic aberrations of one gene can result in many different phenotypes.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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