title: Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes.
abstract: OBJECTIVE
  PAX4 R192H polymorphism was reported to be associated with maturity onset diabetes of the young (MODY) and early onset-age of type 2 diabetes (T2D). This study aimed to evaluate transcriptional repression activity of PAX4 R192H polymorphism on its target promoters comparing with wild-type PAX4.
  
  
  METHODS
  Wild-type PAX4 and PAX4 R192H proteins were expressed in vitro and the cell compartmentalization of each protein was examined after transfection of the plasmid constructs into βTC3 cells followed by Western-blot analysis. The plasmid containing wild-type PAX4 or PAX4 R192H was co-transfected into βTC3 and αTC-1.9 cells with insulin or glucagon promoter-reporter construct. Transcriptional repression activities were then determined by dual-luciferase reporter assay.
  
  
  RESULTS
  Wild-type PAX4 and PAX4 R192H, which were found to be equally expressed in vitro and transfection systems, were present in the nuclear compartment. Transcriptional repressor activities of PAX4 R192H on human insulin and glucagon promoters were reduced when they were compared with those of wild-type PAX4.
  
  
  CONCLUSIONS
  These results suggested that PAX4 R192H polymorphism generated a protein with defect in transcriptional repressor activities on its target genes, which may lead to β-cell dysfunction associated with MODY and early onset-age of T2D as reported in our previous study.
authors.affiliation: Department of Physiology, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. S_kooptiwut@hotmail.com
authors.forename: Suwattanee
authors.initials: S
authors.lastname: Kooptiwut
authors.forename: Nattachet
authors.initials: N
authors.lastname: Plengvidhya
authors.forename: Titikan
authors.initials: T
authors.lastname: Chukijrungroat
authors.forename: Jatuporn
authors.initials: J
authors.lastname: Sujjitjoon
authors.forename: Namoiy
authors.initials: N
authors.lastname: Semprasert
authors.forename: Hiroto
authors.initials: H
authors.lastname: Furuta
authors.forename: Pa-thai
authors.initials: PT
authors.lastname: Yenchitsomanus
mesh_terms: D017668:Age of Onset; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D005934:Glucagon