Journal article
An unusual class of PITX2 mutations in axenfeld-rieger syndrome
Birth defects research. A Clinical and molecular teratology, Vol.76(3), pp.175-181
2006
DOI: 10.1002/bdra.20226
PMCID: PMC4023635
PMID: 16498627
Abstract
Background: Mutations in the PITX2 homeobox gene are known to contribute to Axenfeld-Rieger syndrome (ARS), an autosomal-dominant developmental disorder. Although most mutations are in the homeodomain and result in a loss of function, there is a growing subset in the C-terminal domain that has not yet been characterized. These mutations are of particular interest because the C-terminus has both inhibitory and stimulatory activities.
Methods: In this study we used a combination of in vitro DNA binding and transfection reporter assays to investigate the fundamental issue of whether C-terminal mutations result in gain or loss of function at a cellular level.
Results: We report a new frameshift mutation in the PITX2 allele that predicts a truncated protein lacking most of the C-terminal domain (D122FS). This newly reported mutant and another ARS C-terminal mutant (W133Stop) both have greater binding than wild-type to the bicoid element. Of interest, the mutants yielded approximately 5-fold greater activation of the prolactin promoter in CHO cells, even though the truncated proteins were expressed at lower levels than the wild-type protein. The truncated proteins also had greater than wild-type activity in 2 other cell lines, including the LS8 oral epithelial line that expresses the endogenous Pitx2 gene.
Conclusions: The results indicate that the PITX2 C-terminal domain has inhibitory activity and support the notion that ARS may also be caused by gain-of-function mutations.
Details
- Title: Subtitle
- An unusual class of PITX2 mutations in axenfeld-rieger syndrome
- Creators
- Irfan SAADI - Genetics Program, University of Iowa, Iowa City, Iowa, United StatesRafael TORO - Genetics Program, University of Iowa, Iowa City, Iowa, United StatesAdisa KUBURAS - Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United StatesElena SEMINA - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesJeffrey C MURRAY - Genetics Program, University of Iowa, Iowa City, Iowa, United StatesAndrew F RUSSO - Genetics Program, University of Iowa, Iowa City, Iowa, United States
- Resource Type
- Journal article
- Publication Details
- Birth defects research. A Clinical and molecular teratology, Vol.76(3), pp.175-181
- DOI
- 10.1002/bdra.20226
- PMID
- 16498627
- PMCID
- PMC4023635
- NLM abbreviation
- Birth Defects Res A Clin Mol Teratol
- ISSN
- 1542-0752
- eISSN
- 1542-0760
- Publisher
- Wiley; Hoboken, NJ
- Language
- English
- Date published
- 2006
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984020649602771
Metrics
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