Altered G-Protein Transduction Protein Gene Expression in the Testis of Infertile Patients with Nonobstructive Azoospermia

DNA Cell Biol. 2023 Oct;42(10):617-637. doi: 10.1089/dna.2023.0189. Epub 2023 Aug 22.

Abstract

Recent studies have shown that several members of the G-protein-coupled receptors (GPCR) superfamily play crucial roles in the maintenance of ion-water homeostasis of the sperm and Sertoli cells, development of the germ cells, formation of the blood barrier, and maturation of sperm. The GPCR, guanyl-nucleotide exchange factor, membrane traffic protein, and small GTPase genes were analyzed by microarray and bioinformatics (3513 sperm and Sertoli cell genes). In the microarray analyses of three human cases with different nonobstructive azoospermia sperm, the expression of GOLGA8IP, OR2AT4, PHKA1, A2M, OR56A1, SEMA3G, LRRC17, APP, ARHGAP33, RABGEF1, NPY2R, GHRHR, LTB4R2, GRIK5, OR6K6, NAPG, OR6C65, VPS35, FPR3, and ARL4A was upregulated, while expression of MARS, SIRPG, OGFR, GPR150, LRRK1, and NGEF was downregulated. There was an increase in GBP3, GBP3, TNF, TGFB3, and CLTC expression in the Sertoli cells of three human cases with NOA, whereas expression of PAQR4, RRAGD, RAC2, SERPINB8, IRPB1, MRGPRF, RASA2, SIRPG, RGS2, RAP2A, RAB2B, ARL17, SERINC4, XIAP, DENND4C, ANKRA2, CSTA, STX18, and SNAP23 were downregulated. A combined analysis of Enrich Shiny Gene Ontology (GO), STRING, and Cytoscape was used to predict proteins' molecular interactions and then to recognize master pathways. Functional enrichment analysis showed that the biological process (BP), regulation of protein metabolic process, regulation of small GTPase-mediated signal transduction were significantly expressed in up-/downregulated differentially expressed genes (DEGs) in sperm. In molecular function (MF) experiments of DEGs that were up-/downregulated, it was found that GPCR activity, guanyl ribonucleotide binding, GTPase activity and nucleoside-triphosphatase activity were overexpressed. An analysis of GO enrichment findings of Sertoli cells showed BP and MF to be common DEGs. When these gene mutations have been validated, they can be used to create new GPCR antagonists or agonists that are receptor-selective.

Keywords: G-protein; Sertoli cell; azoospermia; microarray; sperm.

MeSH terms

  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism
  • Ankyrins / genetics
  • Ankyrins / metabolism
  • Azoospermia* / genetics
  • Azoospermia* / metabolism
  • GTP-Binding Proteins / genetics
  • Gene Expression
  • Humans
  • Male
  • Monomeric GTP-Binding Proteins* / genetics
  • Monomeric GTP-Binding Proteins* / metabolism
  • Semen / metabolism
  • Testis / metabolism
  • rap GTP-Binding Proteins / genetics
  • rap GTP-Binding Proteins / metabolism
  • ras GTPase-Activating Proteins / genetics

Substances

  • Monomeric GTP-Binding Proteins
  • GTP-Binding Proteins
  • RASA2 protein, human
  • ras GTPase-Activating Proteins
  • ANKRA2 protein, human
  • Ankyrins
  • ARL4A protein, human
  • ADP-Ribosylation Factors
  • RAP2A protein, human
  • rap GTP-Binding Proteins
  • OR2AT4 protein, human
  • RABGEF1 protein, human

Supplementary concepts

  • Azoospermia, Nonobstructive