Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 2001 Jun 22;276(25):23034-41
Date
04/13/2001Pubmed ID
11301317DOI
10.1074/jbc.M008592200Scopus ID
2-s2.0-0035933856 (requires institutional sign-in at Scopus site) 77 CitationsAbstract
Mutations in the PITX2 bicoid-like homeobox gene cause Rieger syndrome. Rieger syndrome is an autosomal-dominant human disorder characterized by glaucoma as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities. PITX2 has also been implicated in the development of multiple organs and left-right asymmetry in the body plan. The PITX2 homeodomain has a lysine at position 50, which has been shown to impart the bicoid-type (TAATCC) DNA binding specificity to other homeodomain proteins. A mutation (K88E), found in a Rieger syndrome patient, changes this lysine to glutamic acid. We were intrigued by the relatively pronounced phenotypic consequences of this K88E mutation. In the initial analyses, the mutant protein appeared to simply be inactive, with essentially no DNA binding and transactivation activities and, unlike the wild type protein, with an inability to synergize with another transcription factor, Pit-1. However, when the K88E DNA was cotransfected with wild type PITX2, analogous to the patient genotype, the K88E mutant suppressed the synergism of wild type PITX2 with Pit-1. In contrast, a different PITX2 homeodomain mutant, T68P, which is also defective in DNA binding, transactivation, and Pit-1 synergism activities, did not suppress the wild type synergism with Pit-1. These results describe the first dominant negative missense mutation in a homeodomain and support a model that may partially explain the phenotypic variation within Rieger syndrome.
Author List
Saadi I, Semina EV, Amendt BA, Harris DJ, Murphy KP, Murray JC, Russo AFAuthor
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Abnormalities, MultipleDNA
DNA-Binding Proteins
Genes, Dominant
Homeodomain Proteins
Humans
Infant, Newborn
Mutation
Protein Binding
Syndrome
Transcription Factor Pit-1
Transcription Factors