In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation
Open Access
- 8 December 2004
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 14 (3), 411-420
- https://doi.org/10.1093/hmg/ddi037
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. First, phenotype producing mutations in human and in mouse ZIC2 were mimicked and secondly, a comparative sequence analysis of the C-terminal 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. In addition, the analysis reveals that the C-terminal 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.This publication has 26 references indexed in Scilit:
- Overlapping and distinct expression domains of Zic2 and Zic3 during mouse gastrulationGene Expression Patterns, 2004
- Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformationNature Genetics, 2004
- Molecular screening ofSHH,ZIC2,SIX3, andTGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlationsHuman Mutation, 2004
- Mouse Zic5 deficiency results in neural tube defects and hypoplasia of cephalic neural crest derivativesDevelopmental Biology, 2004
- Alanine tracts: the expanding story of human illness and trinucleotide repeatsTrends in Genetics, 2004
- Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephalyHuman Genetics, 2001
- Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-pairedNature Genetics, 1998
- MouseZic1Is Involved in Cerebellar DevelopmentJournal of Neuroscience, 1998
- The Expression of the MouseZic1, Zic2,andZic3Gene Suggests an Essential Role forZicGenes in Body Pattern FormationDevelopmental Biology, 1997
- Perspectives on holoprosencephaly: Part III. Spectra, distinctions, continuities, and discontinuitiesAmerican Journal of Medical Genetics, 1989