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Human Molecular Genetics, 2002, Vol. 11, No. 7 743-753
© 2002 Oxford University Press

A molecular basis for differential developmental anomalies in Axenfeld–Rieger syndrome

Herbert M. Espinoza, Carol J. Cox, Elena V. Semina1 and Brad A. Amendt+

Department of Biological Sciences, The University of Tulsa, 600 South College Avenue, Tulsa, OK 74104-3189, USA and 1Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USA

Pitx2, a bicoid-like homeodomain transcription factor and Dlx2 are two transcriptional markers observed during early tooth development. PITX2 binds to bicoid and bicoid-like elements in the Dlx2 promoter and activates this promoter 30-fold in Chinese hamster ovary cells. Mutations in PITX2 associated with Axenfeld–Rieger syndrome (ARS) provided the first link of this homeodomain transcription factor to tooth development. We are investigating the molecular basis of developmental anomalies associated with human PITX2 mutations. A phenotypically less severe ARS mutant (without tooth anomalies), PITX2 R84W, has a similar DNA binding specificity compared to wild-type PITX2 and transactivates the Dlx2 promoter. This mutation is associated with iris hypoplasia (IH); in contrast a Rieger syndrome mutation, PITX2 T68P, which presents clinically with the full spectrum of developmental anomalies (including tooth anomalies), is unable to transactivate the Dlx2 promoter. Since Dlx2 expression is required for tooth and craniofacial development the lack of tooth anomalies in the patient with IH may be due to the residual activity of this mutant in activating the Dlx2 promoter. We demonstrate that PITX2 phosphorylation increases PITX2 and PITX2 R84W DNA binding. The PITX2 T68P ARS mutation occurs at a protein kinase C phosphorylation site in the homeodomain. Surprisingly, phosphorylation of PITX2 T68P is increased compared to wild-type PITX2 but has little effect on its DNA binding activity. Altogether these data suggest a molecular mechanism for tooth development involving Dlx2 gene expression in ARS patients.

+ To whom correspondence should be addressed. Tel: +1 918 631 3328; Fax: +1 918 631 2762; Email: brad-amendt@utulsa.edu


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