Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abnormalities, Multiple / genetics*
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Abnormalities, Multiple / physiopathology
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Animals
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Base Sequence
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Cell Line
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Chromatin / metabolism
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Cricetinae
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Ehlers-Danlos Syndrome / genetics
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Ehlers-Danlos Syndrome / physiopathology
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Gene Expression Regulation, Enzymologic
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Genes, Reporter / genetics
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Homeobox Protein PITX2
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Mice
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Molecular Sequence Data
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Multigene Family / genetics*
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Nuclear Proteins*
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Paired Box Transcription Factors
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Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics*
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Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / metabolism
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Recombinant Fusion Proteins / metabolism
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Regulatory Sequences, Nucleic Acid / genetics*
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Syndrome
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Chromatin
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Homeodomain Proteins
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Nuclear Proteins
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Paired Box Transcription Factors
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Recombinant Fusion Proteins
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Transcription Factors
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homeobox protein PITX1
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homeobox protein PITX3
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Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
Associated data
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GENBANK/AF081786
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GENBANK/AF283255