GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes

Disorders of sex development (DSD) consist of a wide range of conditions involving numerous genes. Nevertheless, about half of 46,XY individuals remain genetically unsolved. GATA4 gene variants, mainly related to congenital heart defects (CHD), have also been recently associated with 46,XY DSD. In t...

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Main Authors: Idoia Martinez de LaPiscina, Carmen de Mingo, Stefan Riedl, Amaia Rodriguez, Amit V. Pandey, Mónica Fernández-Cancio, Nuria Camats, Andrew Sinclair, Luis Castaño, Laura Audi, Christa E. Flück
Format: Article
Language:English
Published: Frontiers Media S.A. 2018-04-01
Series:Frontiers in Endocrinology
Subjects:
DSD
Online Access:http://journal.frontiersin.org/article/10.3389/fendo.2018.00142/full
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author Idoia Martinez de LaPiscina
Idoia Martinez de LaPiscina
Idoia Martinez de LaPiscina
Carmen de Mingo
Stefan Riedl
Amaia Rodriguez
Amit V. Pandey
Amit V. Pandey
Mónica Fernández-Cancio
Nuria Camats
Andrew Sinclair
Luis Castaño
Luis Castaño
Laura Audi
Christa E. Flück
Christa E. Flück
spellingShingle Idoia Martinez de LaPiscina
Idoia Martinez de LaPiscina
Idoia Martinez de LaPiscina
Carmen de Mingo
Stefan Riedl
Amaia Rodriguez
Amit V. Pandey
Amit V. Pandey
Mónica Fernández-Cancio
Nuria Camats
Andrew Sinclair
Luis Castaño
Luis Castaño
Laura Audi
Christa E. Flück
Christa E. Flück
GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes
Frontiers in Endocrinology
disorder of sexual development
DSD
GATA4
congenital heart defects
oligogenic
46,XY DSD
author_facet Idoia Martinez de LaPiscina
Idoia Martinez de LaPiscina
Idoia Martinez de LaPiscina
Carmen de Mingo
Stefan Riedl
Amaia Rodriguez
Amit V. Pandey
Amit V. Pandey
Mónica Fernández-Cancio
Nuria Camats
Andrew Sinclair
Luis Castaño
Luis Castaño
Laura Audi
Christa E. Flück
Christa E. Flück
author_sort Idoia Martinez de LaPiscina
title GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes
title_short GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes
title_full GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes
title_fullStr GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes
title_full_unstemmed GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes
title_sort gata4 variants in individuals with a 46,xy disorder of sex development (dsd) may or may not be associated with cardiac defects depending on second hits in other dsd genes
publisher Frontiers Media S.A.
series Frontiers in Endocrinology
issn 1664-2392
publishDate 2018-04-01
description Disorders of sex development (DSD) consist of a wide range of conditions involving numerous genes. Nevertheless, about half of 46,XY individuals remain genetically unsolved. GATA4 gene variants, mainly related to congenital heart defects (CHD), have also been recently associated with 46,XY DSD. In this study, we characterized three individuals presenting with 46,XY DSD with or without CHD and GATA4 variants in order to understand the phenotypical variability. We studied one patient presenting CHD and 46,XY gonadal dysgenesis, and two patients with a history of genetically unsolved 46,XY DSD, also known as male primary hypogonadism. Mutation analysis was carried out by candidate gene approach or targeted gene panel sequencing. Functional activity of GATA4 variants was tested in vitro on the CYP17 promoter involved in sex development using JEG3 cells. We found two novel and one previously described GATA4 variants located in the N-terminal zinc finger domain of the protein. Cys238Arg variant lost transcriptional activity on the CYP17 promoter reporter, while Trp228Cys and Pro226Leu behaved similar to wild type. These results were in line with bioinformatics simulation studies. Additional DSD variations, in the LRP4 and LHCGR genes, respectively, were identified in the two 46,XY individuals without CHD. Overall, our study shows that human GATA4 mutations identified in patients with 46,XY DSD may or may not be associated with CHD. Possible explanations for phenotypical variability may comprise incomplete penetrance, variable sensitivity of partner genes, and oligogenic mechanisms.
topic disorder of sexual development
DSD
GATA4
congenital heart defects
oligogenic
46,XY DSD
url http://journal.frontiersin.org/article/10.3389/fendo.2018.00142/full
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spelling doaj-5e681134d0a249e4ae755fdd6e35b7a22020-11-24T23:48:04ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922018-04-01910.3389/fendo.2018.00142344423GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD GenesIdoia Martinez de LaPiscina0Idoia Martinez de LaPiscina1Idoia Martinez de LaPiscina2Carmen de Mingo3Stefan Riedl4Amaia Rodriguez5Amit V. Pandey6Amit V. Pandey7Mónica Fernández-Cancio8Nuria Camats9Andrew Sinclair10Luis Castaño11Luis Castaño12Laura Audi13Christa E. Flück14Christa E. Flück15Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, SpainPediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandPediatric Endocrinology, Diabetology and Metabolism, Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandPediatric Endocrinology, La Fe Pediatric University Hospital, Valencia, SpainDivision of Pediatric Pulmology, Allergology, and Endocrinology, St. Anna Children’s Hospital, Department of Pediatrics, Medical University of Vienna, Vienna, AustriaPediatric Endocrinology Section, Cruces University Hospital, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV/EHU, Barakaldo, SpainPediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandPediatric Endocrinology, Diabetology and Metabolism, Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandGrowth and Development Research, Pediatric Endocrinology Unit, Vall d’Hebron Research Institute (VHIR), CIBERER, Instituto de Salud Carlos III, Barcelona, SpainGrowth and Development Research, Pediatric Endocrinology Unit, Vall d’Hebron Research Institute (VHIR), CIBERER, Instituto de Salud Carlos III, Barcelona, SpainDepartment of Paediatrics, Murdoch Children’s Research Institute, University of Melbourne, The Royal Children’s Hospital, Melbourne, VIC, AustraliaEndocrinology and Diabetes Research Group, BioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, SpainPediatric Endocrinology Section, Cruces University Hospital, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV/EHU, Barakaldo, SpainGrowth and Development Research, Pediatric Endocrinology Unit, Vall d’Hebron Research Institute (VHIR), CIBERER, Instituto de Salud Carlos III, Barcelona, SpainPediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandPediatric Endocrinology, Diabetology and Metabolism, Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDisorders of sex development (DSD) consist of a wide range of conditions involving numerous genes. Nevertheless, about half of 46,XY individuals remain genetically unsolved. GATA4 gene variants, mainly related to congenital heart defects (CHD), have also been recently associated with 46,XY DSD. In this study, we characterized three individuals presenting with 46,XY DSD with or without CHD and GATA4 variants in order to understand the phenotypical variability. We studied one patient presenting CHD and 46,XY gonadal dysgenesis, and two patients with a history of genetically unsolved 46,XY DSD, also known as male primary hypogonadism. Mutation analysis was carried out by candidate gene approach or targeted gene panel sequencing. Functional activity of GATA4 variants was tested in vitro on the CYP17 promoter involved in sex development using JEG3 cells. We found two novel and one previously described GATA4 variants located in the N-terminal zinc finger domain of the protein. Cys238Arg variant lost transcriptional activity on the CYP17 promoter reporter, while Trp228Cys and Pro226Leu behaved similar to wild type. These results were in line with bioinformatics simulation studies. Additional DSD variations, in the LRP4 and LHCGR genes, respectively, were identified in the two 46,XY individuals without CHD. Overall, our study shows that human GATA4 mutations identified in patients with 46,XY DSD may or may not be associated with CHD. Possible explanations for phenotypical variability may comprise incomplete penetrance, variable sensitivity of partner genes, and oligogenic mechanisms.http://journal.frontiersin.org/article/10.3389/fendo.2018.00142/fulldisorder of sexual developmentDSDGATA4congenital heart defectsoligogenic46,XY DSD