Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability.
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.
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Stephen R F
SR
Twigg
Department of Cell Biology and Neuroscience, 513 Leon Johnson Hall, Montana State University, Bozeman, MT 59717, USA.
Jennifer
J
Forecki
Department of Plastic Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Jacqueline A C
JA
Goos
Developmental Biology and Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Ivy C A
IC
Richardson
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
A Jeannette M
AJ
Hoogeboom
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Ans M W
AM
van den Ouweland
Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Sigrid M A
SM
Swagemakers
Department of Pediatric Radiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Maarten H
MH
Lequin
Department of Cell Biology and Neuroscience, 513 Leon Johnson Hall, Montana State University, Bozeman, MT 59717, USA.
Daniel
D
Van Antwerp
Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Simon J
SJ
McGowan
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Isabelle
I
Westbury
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Kerry A
KA
Miller
Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Steven A
SA
Wall
Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Peter J
PJ
van der Spek
Department of Plastic Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Irene M J
IM
Mathijssen
Developmental Biology and Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Erwin
E
Pauws
Department of Cell Biology and Neuroscience, 513 Leon Johnson Hall, Montana State University, Bozeman, MT 59717, USA.
Christa S
CS
Merzdorf
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: andrew.wilkie@imm.ox.ac.uk.
Andrew O M
AO
Wilkie
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D018389:Codon, Nonsense / Q000235:genetics*; D003398:Craniosynostoses / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007621:Karyotyping; D007859:Learning Disabilities / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014982:Xenopus laevis; D000099266:Engrailed 2 Protein
D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000099266:Engrailed 2 Protein; C492123:ZIC1 protein, human