A Novel De novo GATA-binding Protein 3 Mutation in a Patient with Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia Syndrome

INTRODUCTION Hypoparathyroidism, sensorineural deafness, and renal dysplasia （HDR） syndrome, also called Barakat syndrome, is an autosomal dominant genetic disease caused by haploinsufficiency of the GATA-binding protein 3 （GATA3） gene located on the 10pl 5 chromosome.

Nucleus Pulposus Cells from Calcified Discs Promote the Degradation of the Extracellular Matrix through Upregulation of the GATA3 Expression

Objective Disc calcification is strongly associated with disc degeneration;however,the underlying mechanisms driving its pathogenesis are poorly understood.This study aimed to provide a gene expression profile of nucleus pulposus cells(NPCs)from calcified discs,and clarify the potential mechanism in disc degeneration.Methods Primary NPCs were isolated from calcified and control discs(CAL-NPC and CON-NPC),respectively.The proliferation and extracellular matrix(ECM)metabolism capacities of the cells were evaluated using MTT and Western blotting,respectively.RNA sequencing was used to identify differentially expressed genes(DEGs)in the CAL-NPCs.The biological functions of the DEGs were analyzed using the Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)databases.The transcription factor database and Cytoscape software were used to construct the transcription factor-DEGs regulatory network.The role of the verified transcription factor in NPC proliferation and ECM metabolism was also investigated.Results The CAL-NPCs exhibited a lower proliferation rate and higher ECM degradation capacity than the CON-NPCs.In total,375 DEGs were identified in the CAL-NPCs.The GO and KEGG analyses showed that the DEGs were primarily involved in the regulation of ribonuclease activity and NF-kappa B and p53 signaling pathways.GATA-binding protein 3(GATA3)with the highest verified levels was selected for further studies.Overexpression of GATA3 in the CON-NPCs significantly inhibited their proliferation and promoted their ECM degradation function,while the knockdown of GATA3 in the CAL-NPCs resulted in the opposite phenotypes.Conclusion This study provided a comprehensive gene expression profile of the NPCs from the calcified discs and supported that GATA3 could be a potential target for reversing calcification-associated disc degeneration.

Mutational analysis of the GATA4 gene in Chinese men with nonobstructive azoospermia

As a crucial transcription factor for spermatogenesis,GATA-binding protein 4(GATA4)plays important roles in the functioning of Sertoli and Leydig cells.Conditional knockout of GATA4 in mice results in age-dependent testicular atrophy and loss of fertility.However,whether GATA4 is associated with human azoospermia has not been reported.Herein,we analyzed the GATA4 gene by direct sequencing of samples obtained from 184 Chinese men with idiopathic nonobstructive azoospermia(NOA).We identified a missense mutation(c.191G>A,p.G64E),nine single-nucleotide polymorphisms(SNPs),and one rare variant(c.^(*)84C>T)in the 3′untranslated region(UTR).Functional studies demonstrated that the p.G64E mutation did not affect transactivation ability of GATA4 for spermatogenesis-related genes(claudin-11 and steroidogenic acute regulatory protein,Star),and the 3′UTR rare variant c.^(*)84C>T did not generate microRNA-binding sites to repress GATA4 expression.To our knowledge,this is the first report to investigate the association between GATA4 and azoospermia;our results indicate that mutations in GATA4 may not be pathogenic for NOA in Chinese men.