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Human Molecular Genetics Advance Access published online on December 8, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi037
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Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved

Article

In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation

Lucia Brown 1, Melinda Paraso 1, Ruth Arkell 2, and Stephen Brown 1*

1 Dept. of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York
2 Early Development, Mammalian Genetics Unit, MRC, Harwell, Oxfordshire

* To whom correspondence should be addressed.
Stephen Brown, E-mail: sab8{at}columbia.edu


  Abstract

Heterozygous loss of function mutations in ZIC2 result in the severe brain malformation known as holoprosencephaly (HPE), indicating that forebrain development is exquisitely sensitive to the activity of this poorly understood transcription factor. To identify the regions of ZIC2 that are essential for activity we have assessed the ability of a variety of ZIC2 mutant proteins to function in in-vitro assays. Two sources of information were used to design relevant mutations. Firstly, phenotype producing mutations in human and mouse ZIC2 were mimicked and secondly a comparative sequence analysis of the c-terminus was carried out. Analysis of these mutations suggests that either a decrease or an increase in ZIC2 mediated transcriptional activity can produce a forebrain phenotype. Additionally, the analysis reveals that the C-terminus of ZIC2 contains both activation and repression domains. This region of ZIC2 contains an alanine-tract and expansion of this domain is associated with HPE. In-vitro analysis of proteins with alterations in alanine-tract length illustrates that the c-terminal alanine-tract of ZIC2 influences the strength of DNA binding and alters transcriptional activity in a promoter specific manner. This finding provides a possible mechanism by which alanine-tract expansion mutations could alter the function of other transcription factors.


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