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.

Idoia Martinez De Lapiscina,Laura Audi,Nuria Camats,Luis Castaño,Carmen De Mingo,Amit V Pandey,Andrew Sinclair,Amaia Rodriguez,Christa E Flück,Stefan Riedl,Mónica Fernández-Cancio

doi:10.3389/fendo.2018.00142

Abstract

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.

Highlights

Disorders of sex development (DSD) are defined as congenital conditions, in which development of chromosomal, gonadal, or anatomical sex is atypical [1]. 46,XY DSD includes disorders in male gonad determination and differentiation, androgen biosynthesis or action, and anti-Müllerian hormone (AMH) synthesis or action [1]
Biochemical and hormonal studies at presentation and during follow-up revealed more or less normal values, only undetectable and low AMH was remarkable (Table 2). She was seen by a pediatric cardiologist for a heart murmur and found to have a complex congenital heart defects (CHD), which was not detected in prenatal screening (Table 1)
We characterized three human GATA4 sequence variations found in three individuals with a 46,XY DSD phenotype with and without CHD

Summary

Introduction

Disorders of sex development (DSD) are defined as congenital conditions, in which development of chromosomal, gonadal, or anatomical sex is atypical [1]. 46,XY DSD includes disorders in male gonad determination and differentiation, androgen biosynthesis or action, and anti-Müllerian hormone (AMH) synthesis or action [1]. Disorders of sex development (DSD) are defined as congenital conditions, in which development of chromosomal, gonadal, or anatomical sex is atypical [1]. 46,XY DSD includes disorders in male gonad determination and differentiation, androgen biosynthesis or action, and anti-Müllerian hormone (AMH) synthesis or action [1]. In the last two decades, numerous genes have been found to cause 46,XY DSD [2]. In about 40% of 46,XY DSD individuals, the underlying genetic cause still remains unsolved. The GATA family of transcription factors consists of six members, three expressed in hematopoietic stem cells (GATA1–3) and three in tissues derived from mesoderm and endoderm, including heart, gonad, lung, liver, and gut (GATA4–6). GATA factors regulate tissue-specific gene expression either alone or in cooperation with other factors [3, 4]. While the C-terminal zinc finger region is required for the DNA recognition and binding, and the N-terminal zinc finger region contributes to the stability, both zinc fingers are necessary for protein–protein interactions with other transcription factors [4, 7]

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