Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development.

Jocelyn A Van Den Bergen,Chris Kimber,Sophy Khan,Gorjana Robevska,Vincent Harley,Susan R Davis,Sultana M H Faradz,Sonia R Grover,Irum Atta,Csilla Krausz,Jamal Raza,Ashish Jiwane,Stefan Riedl,Makato Ono,Philip B Bergman,Katie L Ayers,Stefanie Eggers,Andrew H Sinclair

doi:10.1002/mgg3.1095

Abstract

BackgroundGATA‐binding protein 4 (GATA4) and Friend of GATA 2 protein (FOG2, also known as ZFPM2) form a heterodimer complex that has been shown to influence transcription of genes in a number of developmental systems. Recent evidence has also shown these genes play a role in gonadal sexual differentiation in humans. Previously we identified four variants in GATA4 and an unexpectedly large number of variants in ZFPM2 in a cohort of individuals with 46,XY Differences/Disorders of Sex Development (DSD) (Eggers et al, Genome Biology, 2016; 17: 243).MethodHere, we review variant curation and test the functional activity of GATA4 and ZFPM2 variants. We assess variant transcriptional activity on gonadal specific promoters (Sox9 and AMH) and variant protein–protein interactions.ResultsOur findings support that the majority of GATA4 and ZFPM2 variants we identified are benign in their contribution to 46,XY DSD. Indeed, only one variant, in the conserved N‐terminal zinc finger of GATA4, was considered pathogenic, with functional analysis confirming differences in its ability to regulate Sox9 and AMH and in protein interaction with ZFPM2.ConclusionsOur study helps define the genetic factors contributing to 46,XY DSD and suggests that the majority of variants we identified in GATA4 and ZFPM2/FOG2 are not causative.

Highlights

The GATA zinc finger transcription factors (1–6) are an evolutionally conserved family that plays various roles in embryonic development
Our findings support that the majority of GATA-binding protein 4 (GATA4) and ZFPM2 variants we identified are benign in their contribution to 46,XY Disorders of Sex Development (DSD)
Our study helps define the genetic factors contributing to 46,XY DSD and suggests that the majority of variants we identified in GATA4 and ZFPM2/FOG2 are not causative

Summary

| INTRODUCTION

The GATA zinc finger transcription factors (1–6) are an evolutionally conserved family that plays various roles in embryonic development. In 2011, a heterozygous missense variant in the GATA4 gene was identified in a family with two affected brothers, one presented with ambiguous genitalia and inguinal hernia at birth, the other was diagnosed later in life to have testicular anomalies (Lourenco et al, 2011). The variant c.661G > A (p.G221R) was located in the N-terminal zinc finger domain and had reduced DNA binding and transcriptional activity, as well as reduced interaction with co-factor protein ZFPM2/FOG2 (Lourenco et al, 2011). While screening 279 46,XY DSD individuals for variants in genes known to cause DSD, we previously identified four variants in GATA4 and 10 variants in ZFPM2 in 16 patients (Eggers et al, 2016) This was a surprisingly large number of variants for ZFPM2 considering only one paper van den BERGEN et al. We have re-curated these GATA4 and ZFPM2 variants using updated tools, and have tested their molecular activity in the context of gonadal signaling using several in vitro assays

| RESULTS

| DISCUSSION

Findings

| MATERIALS AND METHODS