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 ocula r, craniofacial, and umbilical defects. Patients have mutations in PITX2, a paired-bicoid homeobox gene, also involved in left/right polarity determin ation. In this study we have identified a family of genes for enzymes respo nsible for hydroxylizing lysines in collagens as one group of likely cognat e 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 promo ters, contains multiple bicoid (PITX2) binding elements. We show these elem ents to bind PITX2 specifically in vitro. The PLOD-1 promoter induces the e xpression of a luciferase reporter gene in the presence of PITX2 in cotrans fection experiments. The Rieger syndrome causing PITX2 mutant T68P fails to induce PLOD-l-luciferase. Mutations and rearrangements in PLOD-1 are known to be prevalent in patients with Ehlers-Danlos syndrome, kyphoscoliosis ty pe (type VI [EDVI]). Several of the same organ systems are involved in Rieg er syndrome and EDVI.