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Open Access Research article

Functional analysis of human mutations in homeodomain transcription factor PITX3

Satoru Sakazume123, Elena Sorokina124, Yoshiki Iwamoto256 and Elena V Semina124*

Author Affiliations

1 Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

2 Human and Molecular Genetics Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

3 Division of Clinical Genetics, Gunma Children's Medical Center, Shibukawa, Gunma, Japan

4 Children's Research Institute, Children's Hospital of Wisconsin and Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

5 Department of Urology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

6 Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010-3000, USA

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BMC Molecular Biology 2007, 8:84  doi:10.1186/1471-2199-8-84

Published: 21 September 2007

Abstract

Background

The homeodomain-containing transcription factor PITX3 was shown to be essential for normal eye development in vertebrates. Human patients with point mutations in PITX3 demonstrate congenital cataracts along with anterior segment defects in some cases when one allele is affected and microphthalmia with brain malformations when both copies are mutated. The functional consequences of these human mutations remain unknown.

Results

We studied the PITX3 mutant proteins S13N and G219fs to determine the type and severity of functional defects. Our results demonstrate alterations in DNA-binding profiles and/or transactivation activities and suggest a partial loss-of-function in both mutants with the G219fs form being more severely affected. No anomalies in cellular distribution and no dominant-negative effects were discovered for these mutants. Interestingly, the impairment of the G219fs activity varied between different ocular cell lines.

Conclusion

The G219fs mutation was found in multiple families affected with congenital cataracts along with anterior segment malformations in many members. Our data suggest that the presence/severity of anterior segment defects in families affected with G219fs may be determined by secondary factors that are expressed in the developing anterior segment structures and may modify the effect(s) of this mutation. The S13N mutant showed only minor alteration of transactivation ability and DNA binding pattern and may represent a rare polymorphism in the PITX3 gene. A possible contribution of this mutation to human disease needs to be further investigated.