PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome.
The Rieger syndrome is an autosomal dominant disease characterized by ocular, craniofacial, and umbilical defects. Patients have mutations in PITX2, a paired-bicoid homeobox gene, also involved in left/right polarity determination. In this study we have identified a family of genes for enzymes responsible for hydroxylizing lysines in collagens as one group of likely cognate targets of PITX2 transcriptional regulation. The mouse procollagen lysyl hydroxylase (Plod)-2 gene was enriched for by chromatin precipitation using a PITX2/Pitx2-specific antibody. Plod-2, as well as the human PLOD-1 promoters, contains multiple bicoid (PITX2) binding elements. We show these elements to bind PITX2 specifically in vitro. The PLOD-1 promoter induces the expression of a luciferase reporter gene in the presence of PITX2 in cotransfection experiments. The Rieger syndrome causing PITX2 mutant T68P fails to induce PLOD-1-luciferase. Mutations and rearrangements in PLOD-1 are known to be prevalent in patients with Ehlers-Danlos syndrome, kyphoscoliosis type (type VI [EDVI]). Several of the same organ systems are involved in Rieger syndrome and EDVI.
Hjalt
T A
TA
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA.
Amendt
B A
BA
Murray
J C
JC
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D006224:Cricetinae; D004535:Ehlers-Danlos Syndrome / Q000235:genetics / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
D002843:Chromatin; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3