Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability

Am J Hum Genet. 2015 Sep 3;97(3):378-88. doi: 10.1016/j.ajhg.2015.07.007.

Stephen R F Twigg ¹, Jennifer Forecki ², Jacqueline A C Goos ³, Ivy C A Richardson ⁴, A Jeannette M Hoogeboom ⁵, Ans M W van den Ouweland ⁵, Sigrid M A Swagemakers ⁶, Maarten H Lequin ⁷, Daniel Van Antwerp ², Simon J McGowan ⁸, Isabelle Westbury ¹, Kerry A Miller ¹, Steven A Wall ⁹, WGS500 Consortium, Peter J van der Spek ⁶, Irene M J Mathijssen ³, Erwin Pauws ⁴, Christa S Merzdorf ², Andrew O M Wilkie ¹⁰

Affiliations

1 Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
2 Department of Cell Biology and Neuroscience, 513 Leon Johnson Hall, Montana State University, Bozeman, MT 59717, USA.
3 Department of Plastic Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
4 Developmental Biology and Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
5 Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
6 Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
7 Department of Pediatric Radiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
8 Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
9 Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
10 Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address: [email protected].

PMID: 26340333 DOI: 10.1016/j.ajhg.2015.07.007

Abstract

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.