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

American Journal of Human Genetics
Stephen R F TwiggAndrew O M Wilkie

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 s...Continue Reading

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Citations

Sep 5, 2015·American Journal of Human Genetics·Stephen R F Twigg, Andrew O M Wilkie
Mar 24, 2016·Wiley Interdisciplinary Reviews. Developmental Biology·Kevin FlahertyJoan T Richtsmeier
Sep 14, 2016·Frontiers in Neuroscience·Antonio Benítez-BurracoElliot Murphy
Nov 26, 2016·Journal of Medical Genetics·Kerry A MillerAndrew O M Wilkie
Sep 26, 2020·American Journal of Medical Genetics. Part a·Erina SasakiWilliam Reardon
Feb 6, 2017·American Journal of Medical Genetics. Part a·Wanda LattanziSimeon A Boyadjiev
Jun 8, 2019·DNA Research : an International Journal for Rapid Publication of Reports on Genes and Genomes·Zirui DongYuan Jiang
Aug 10, 2019·Communications Biology·Sven J van der LeeCharles DeCarli
Jan 12, 2020·Communications Biology·Sven J van der LeeCharles DeCarli
Sep 26, 2020·Journal of Structural Biology·Amel DudakovicNan E Hatch
Oct 13, 2019·Neuro-Chirurgie·T ArmandM Rossi
Jun 7, 2021·Behavioural Brain Research·Maria M Ortiz-JuzaJose Rodriguez-Romaguera
Nov 13, 2017·ACS Biomaterials Science & Engineering·Zeinab Al-RekabiNathan J Sniadecki

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Methods Mentioned

BETA
biopsies
PCR
electrophoresis
exome sequencing

Software Mentioned

Platypus
Exome Variant Server
ANNOVAR
house script
Stampy
Ion Torrent
SAMtools

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