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GATA transcription factors in testicular adrenal rest tumours.

ABSTRACT: Testicular adrenal rest tumours (TARTs) are benign adrenal-like testicular tumours that frequently occur in male patients with congenital adrenal hyperplasia. Recently, GATA transcription factors have been linked to the development of TARTs in mice. The aim of our study was to determine GATA expression in human TARTs and other steroidogenic tissues. We determined GATA expression in TARTs (n?=?16), Leydig cell tumours (LCTs; n?=?7), adrenal (foetal (n?=?6)?+?adult (n?=?10)) and testis (foetal (n?=?13)?+?adult (n?=?8)). We found testis-like GATA4, and adrenal-like GATA3 and GATA6 gene expressions by qPCR in human TARTs, indicating mixed testicular and adrenal characteristics of TARTs. Currently, no marker is available to discriminate TARTs from LCTs, leading to misdiagnosis and incorrect treatment. GATA3 and GATA6 mRNAs exhibited excellent discriminative power (area under the curve of 0.908 and 0.816, respectively), while immunohistochemistry did not. GATA genes contain several CREB-binding sites and incubation with 0.1?mM dibutyryl cAMP for 4?h stimulated GATA3, GATA4 and GATA6 expressions in a human foetal testis cell line (hs181.tes). Incubation of adrenocortical cells (H295RA) with ACTH, however, did not induce GATA expression in vitro Although ACTH did not dysregulate GATA expression in the only human ACTH-sensitive in vitro model available, our results do suggest that aberrant expression of GATA transcription factors in human TARTs might be involved in TART formation.

SUBMITTER: Engels M

PROVIDER: S-EPMC5682415 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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GATA transcription factors in testicular adrenal rest tumours.

Engels Manon M Span Paul N PN Mitchell Rod T RT Heuvel Joop J T M JJTM Marijnissen-van Zanten Monica A MA van Herwaarden Antonius E AE Hulsbergen-van de Kaa Christina A CA Oosterwijk Egbert E Stikkelbroeck Nike M NM Smith Lee B LB Sweep Fred C G J FCGJ Claahsen-van der Grinten Hedi L HL

Endocrine connections 20171016 8

Testicular adrenal rest tumours (TARTs) are benign adrenal-like testicular tumours that frequently occur in male patients with congenital adrenal hyperplasia. Recently, GATA transcription factors have been linked to the development of TARTs in mice. The aim of our study was to determine GATA expression in human TARTs and other steroidogenic tissues. We determined GATA expression in TARTs (n = 16), Leydig cell tumours (LCTs; n = 7), adrenal (foetal (n = 6) + adult (n = ...[more]

PMID: 29038332

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Project description:GATA transcription factors (TFs) are widespread eukaryotic regulators whose DNA-binding domain is a class IV zinc finger motif (CX2CX17-20CX2C) followed by a basic region. Due to the low cost of genome sequencing, multiple strains of specific species have been sequenced: e.g., number of plant genomes in the Plant Genome Database (http://www.plantgenome.info/) is 2,174 originated from 713 plant species. Thus, we investigated GATA TFs of 19 Arabidopsis thaliana genome-widely to understand intraspecific features of Arabidopsis GATA TFs with the pipeline of GATA database (http://gata.genefamily.info/). Numbers of GATA genes and GATA TFs of each A. thaliana genome range from 29 to 30 and from 39 to 42, respectively. Four cases of different pattern of alternative splicing forms of GATA genes among 19 A. thaliana genomes are identified. 22 of 2,195 amino acids (1.002%) from the alignment of GATA domain amino acid sequences display variations across 19 ecotype genomes. In addition, maximally four different amino acid sequences per each GATA domain identified in this study indicate that these position-specific amino acid variations may invoke intraspecific functional variations. Among 15 functionally characterized GATA genes, only five GATA genes display variations of amino acids across ecotypes of A. thaliana, implying variations of their biological roles across natural isolates of A. thaliana. PCA results from 28 characteristics of GATA genes display the four groups, same to those defined by the number of GATA genes. Topologies of bootstrapped phylogenetic trees of Arabidopsis chloroplasts and common GATA genes are mostly incongruent. Moreover, no relationship between geographical distribution and their phylogenetic relationships was found. Our results present that intraspecific variations of GATA TFs in A. thaliana are conserved and evolutionarily neutral along with 19 ecotypes, which is congruent to the fact that GATA TFs are one of the main regulators for controlling essential mechanisms, such as seed germination and hypocotyl elongation.

Project description:ObjectiveTo analyze the mutational spectrum, clinical characteristics, genotype-phenotype correlations, testicular adrenal rests tumor prevalence, and role of neonatal screening in congenital adrenal hyperplasia (CAH) patients from Slovakia and Slovenia.Design and methodsData were obtained from 104 patients with CAH registered in Slovak and Slovenian databases. Low-resolution genotyping was performed to detect the most common point mutations. To detect deletions, conversions, point mutations, or other sequence changes in the CYP21A2 gene, high-resolution genotyping was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C).Results64% of the individuals had the salt-wasting form (SW-CAH), 15% the simple virilizing form (SV-CAH), and 21% the non-classic (NC-CAH). CYP21A2 gene deletion/conversion and c.293-13A/C>G pathogenic variant accounted together for 55.5% of the affected alleles. In SV-CAH p.Ile172Asn was the most common pathogenic variant (28.13%), while in NC-CAH p.Val282Leu (33.33%), CYP21A2 gene deletion/conversion (21.43%), c.293-13A/C>G (14.29%), Pro30Leu (11.90%). The frequency of alleles with multiple pathogenic variants was higher in Slovenian patients (15.83% of all alleles). Severe genotypes (0 and A) correlated well with the expected phenotype (SW in 94.74% and 97.3%), while less severe genotypes (B and C) correlated weaklier (SV in 50% and NC in 70.8%). The median age of SW-CAH patients at the time of diagnosis was 6 days in Slovakia vs. 28.5 days in Slovenia (p=0.01). Most of the Slovak patients in the cohort were detected by NBS. (24 out of 29). TARTs were identified in 7 out of 24 male patients, of whom all (100%) had SW-CAH and all had poor hormonal control. The median age at the diagnosis of TARTs was 13 years.ConclusionThe study confirmed the importance of neonatal screening, especially in the speed of diagnosis of severe forms of CAH. The prediction of the 21-OH deficiency phenotype was reasonably good in the case of severe pathogenic variants, but less reliable in the case of milder pathogenic variants, which is consistent compared to data from other populations. Screening for TARTs should be realized in all male patients with CAH, since there is possible remission when identified early.

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GATA transcription factors in testicular adrenal rest tumours.

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GATA transcription factors in testicular adrenal rest tumours.

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