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An unusual class of PITX2 mutations in Axenfeld-Rieger syndrome. Birth Defects Res A Clin Mol Teratol 2006 Mar;76(3):175-81

Date

02/25/2006

Pubmed ID

16498627

Pubmed Central ID

PMC4023635

DOI

10.1002/bdra.20226

Scopus ID

2-s2.0-33645512300 (requires institutional sign-in at Scopus site)   26 Citations

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.

Author List

Saadi I, Toro R, Kuburas A, Semina E, Murray JC, Russo AF

Author

Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Abnormalities, Multiple
Animals
Anterior Eye Segment
CHO Cells
Child, Preschool
Cricetinae
Cricetulus
DNA Mutational Analysis
DNA-Binding Proteins
Dimerization
Female
Homeodomain Proteins
Humans
Male
Mice
Mutation
Syndrome
Tooth Abnormalities
Transcription Factors
Transcriptional Activation
Umbilical Cord