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Functional analysis of human mutations in homeodomain transcription factor PITX3. BMC Mol Biol 2007 Sep 21;8:84

Date

09/25/2007

Pubmed ID

17888164

Pubmed Central ID

PMC2093940

DOI

10.1186/1471-2199-8-84

Scopus ID

2-s2.0-36348932775 (requires institutional sign-in at Scopus site)   32 Citations

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.

Author List

Sakazume S, Sorokina E, Iwamoto Y, Semina EV

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
Base Sequence
Cataract
DNA Mutational Analysis
Dogs
Gene Expression Regulation, Developmental
Genes, Homeobox
Genetic Markers
Genetic Predisposition to Disease
Homeodomain Proteins
Humans
Lens, Crystalline
Mice
Microphthalmos
Molecular Sequence Data
Mutation
Nervous System Malformations
Phenotype
Rats
Sequence Alignment
Sequence Homology
Transcription Factors
Transcriptional Activation