Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability
| Autor: | Kerry A. Miller, Jacqueline A C Goos, Christa Merzdorf, Isabelle Westbury, Sigrid M. A. Swagemakers, A. Jeannette M. Hoogeboom, Maarten H. Lequin, Steven A. Wall, Simon J. McGowan, Peter J. van der Spek, Jennifer Forecki, Ans M.W. van den Ouweland, Irene M.J. Mathijssen, Daniel J. Van Antwerp, Erwin Pauws, Ivy C.A. Richardson, Andrew O.M. Wilkie, Stephen R.F. Twigg |
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| Přispěvatelé: | Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, Pathology, Radiology & Nuclear Medicine |
| Rok vydání: | 2015 |
| Předmět: |
Male
Nonsense mutation Molecular Sequence Data Mutation Missense Nerve Tissue Proteins Biology medicine.disease_cause ZIC1 Article Craniosynostosis Exon Craniosynostoses Mice Xenopus laevis medicine Genetics Missense mutation Animals Humans Genetics(clinical) Cloning Molecular Genetics (clinical) In Situ Hybridization Homeodomain Proteins Mutation Coronal craniosynostosis Base Sequence Learning Disabilities Gene Expression Regulation Developmental Sequence Analysis DNA medicine.disease Pedigree medicine.anatomical_structure Phenotype Codon Nonsense Karyotyping Female Coronal suture Transcription Factors |
| Zdroj: | American Journal of Human Genetics, 97(3), 378-388. Cell Press |
| ISSN: | 0002-9297 |
| Popis: | Human ZIC1 (zinc finger protein of cerebellum 1), one of five homologs of the Drosophila pair-rule gene odd-paired, encodes a transcription factor previously implicated in vertebrate brain development. Heterozygous deletions of ZIC1 and its nearby paralog ZIC4 on chromosome 3q25.1 are associated with Dandy-Walker malformation of the cerebellum, and loss of the orthologous Zic1 gene in the mouse causes cerebellar hypoplasia and vertebral defects. We describe individuals from five families with heterozygous mutations located in the final (third) exon of ZIC1 (encoding four nonsense and one missense change) who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. The location of the nonsense mutations predicts escape of mutant ZIC1 transcripts from nonsense-mediated decay, which was confirmed in a cell line from an affected individual. Both nonsense and missense mutations are associated with altered and/or enhanced expression of a target gene, engrailed-2, in a Xenopus embryo assay. Analysis of mouse embryos revealed a localized domain of Zic1 expression at embryonic days 11.5-12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture. We conclude that the human mutations uncover a previously unsuspected role for Zic1 in early cranial suture development, potentially by regulating engrailed 1, which was previously shown to be critical for positioning of the murine coronal suture. The diagnosis of a ZIC1 mutation has significant implications for prognosis and we recommend genetic testing when common causes of coronal synostosis have been excluded. |
| Databáze: | OpenAIRE |
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