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

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          Abstract

          Background

          GATA‐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).

          Method

          Here, 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.

          Results

          Our 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.

          Conclusions

          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.

          Abstract

          We identified a number of 46,XY DSD individuals with variants in GATA4 and FOG2. Variant curation and functional analysis revealed the majority of these variants are not likely to be causative.

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          Most cited references44

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          Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.

          The mammalian Y chromosome acts as a dominant male determinant as a result of the action of a single gene, Sry, whose role in sex determination is to initiate testis rather than ovary development from early bipotential gonads. It does so by triggering the differentiation of Sertoli cells from supporting cell precursors, which would otherwise give follicle cells. The related autosomal gene Sox9 is also known from loss-of-function mutations in mice and humans to be essential for Sertoli cell differentiation; moreover, its abnormal expression in an XX gonad can lead to male development in the absence of Sry. These genetic data, together with the finding that Sox9 is upregulated in Sertoli cell precursors just after SRY expression begins, has led to the proposal that Sox9 could be directly regulated by SRY. However, the mechanism by which SRY action might affect Sox9 expression was not understood. Here we show that SRY binds to multiple elements within a Sox9 gonad-specific enhancer in mice, and that it does so along with steroidogenic factor 1 (SF1, encoded by the gene Nr5a1 (Sf1)), an orphan nuclear receptor. Mutation, co-transfection and sex-reversal studies all point to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate Sox9 and then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Our results open up the field, permitting further characterization of the molecular mechanisms regulating sex determination and how they have evolved, as well as how they fail in cases of sex reversal.
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            GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.

            Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs. Here, we show that isolated cardiac septal defects in a large pedigree were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of Gata4. Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.
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              Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis.

              The zinc finger transcription factor GATA4 has been implicated in heart development based on its early expression in precardiogenic splanchnic mesoderm and its ability to activate the expression of a number of cardiac-specific genes. To determine the role of GATA4 in embryogenesis, we generated mice homozygous for a GATA4 null allele. Homozygous GATA4 null mice arrested in development between E7.0 and E9.5 because of severe developmental abnormalities. Mutant embryos most notably lacked a primitive heart tube and foregut and developed partially outside the yolk sac. In the mutants, the two bilaterally symmetric promyocardial primordia failed to migrate ventrally but instead remained lateral and generated two independent heart tubes that contained differentiated cardiomyocytes. We show that these deformities resulted from a general loss in lateral to ventral folding throughout the embryo. GATA4 is most highly expressed within the precardiogenic splanchnic mesoderm at the posterior lip of the anterior intestinal portal, corresponding to the region of the embryo that undergoes ventral fusion. We propose that GATA4 is required for the migration or folding morphogenesis of the precardiogenic splanchnic mesodermal cells at the level of the AIP.
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                Author and article information

                Contributors
                katie.ayers@mcri.edu.au
                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                10.1002/(ISSN)2324-9269
                MGG3
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                2324-9269
                21 January 2020
                March 2020
                : 8
                : 3 ( doiID: 10.1002/mgg3.v8.3 )
                : e1095
                Affiliations
                [ 1 ] Genetics Murdoch Children's Research Institute Parkville Vic. Australia
                [ 2 ] Research Genomics Murdoch Children's Research Institute Parkville Vic. Australia
                [ 3 ] St. Anna Children's Hospital Medical University of Vienna Vienna Austria
                [ 4 ] Paediatric Department Medical University of Vienna Vienna Austria
                [ 5 ] Department of Paediatric and Adolescent Gynaecology Royal Children's Hospital Melbourne Parkville Vic. Australia
                [ 6 ] Department of Paediatrics University of Melbourne Melbourne Vic. Australia
                [ 7 ] Department of Paediatric Endocrinology and Diabetes Monash Children's Hospital Clayton Vic. Australia
                [ 8 ] Department of Paediatrics Monash University Clayton Vic. Australia
                [ 9 ] Department of Paediatric Urology Monash Children's Hospital Clayton Vic. Australia
                [ 10 ] Department of Urology Sydney Children's Hospital Randwick Randwick NSW Australia
                [ 11 ] Surgical Department Angkor Hospital for Children Siem Reap Cambodia
                [ 12 ] Department of Experimental and Clinical Biomedical Sciences“Mario Serio” University of Florence Firenze Toscana Italy
                [ 13 ] Paediatric Department National Institute of Child Health Karachi City Sindh Pakistan
                [ 14 ] Women's Health Research Program School of Public Health and Preventive Medicine Monash University Melbourne Vic. Australia
                [ 15 ] Department of Paediatrics Tokyo Bay Urayasu Ichikawa Iryo Center Urayasu Chiba Japan
                [ 16 ] Centre for Endocrinology and Metabolism Hudson Institute of Medical Research Clayton Vic. Australia
                [ 17 ] Division of Human Genetics Centre for Biomedical Research Faculty of Medicine Diponegoro University (FMDU) Semarang Indonesia
                Author notes
                [*] [* ] Correspondence

                Katie L. Ayers, Genetics, Murdoch Children's Research Institute, Parkville, Vic., Australia.

                Email: katie.ayers@ 123456mcri.edu.au

                Author information
                https://orcid.org/0000-0002-6840-3186
                Article
                MGG31095
                10.1002/mgg3.1095
                7057099
                31962012
                8d499eef-56b4-44fe-9313-d5a646a297ca
                © 2019 The Murdoch Children's Research Institute. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 November 2019
                : 22 November 2019
                Page count
                Figures: 3, Tables: 1, Pages: 14, Words: 9767
                Funding
                Funded by: National Health and Medical Research Council , open-funder-registry 10.13039/501100000925;
                Award ID: 546517
                Funded by: Diponegoro University , open-funder-registry 10.13039/501100005844;
                Award ID: 042.01.2.400898/2016
                Award ID: 474‐73/UN7.P4.3/PP/2018
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                March 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.7 mode:remove_FC converted:05.03.2020

                disorders of sexual development,fog2,functional analysis,gata4,mutations,zfpm2

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