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Hum Mol Genet. 2016 Apr 1;25(7):1382-91. doi: 10.1093/hmg/ddw020. Epub 2016 Jan 24.

A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma.

Author information

1
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, 6 Center Drive, Bethesda, MD 20892, USA, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
2
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada T6G 2E9.
3
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
4
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, 6 Center Drive, Bethesda, MD 20892, USA.
5
Department of Ophthalmology, University Hospital Zurich, Frauenklinikstrasse 24, Zurich 8091, Switzerland.
6
Unit on Pediatric, Developmental, and Genetic Eye Disease, National Eye Institute, 10 Center Drive, Bethesda, MD 20892, USA.
7
Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, AB, Canada T6G 2H7.
8
Welcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK and.
9
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada T6G 2E9, swaroopa@nei.nih.gov david.fitzpatrick@igmm.ed.ac.uk olehmann@ualberta.ca aw@ualberta.ca.
10
Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, AB, Canada T6G 2H7, Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada T6G 2H7 swaroopa@nei.nih.gov david.fitzpatrick@igmm.ed.ac.uk olehmann@ualberta.ca aw@ualberta.ca.
11
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK, swaroopa@nei.nih.gov david.fitzpatrick@igmm.ed.ac.uk olehmann@ualberta.ca aw@ualberta.ca.
12
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, 6 Center Drive, Bethesda, MD 20892, USA, swaroopa@nei.nih.gov david.fitzpatrick@igmm.ed.ac.uk olehmann@ualberta.ca aw@ualberta.ca.

Abstract

Ocular coloboma is a common eye malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lacks the transmembrane domain. The truncated protein was secreted from cells, and behaved as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling. Expression of the resultant mutant protein caused coloboma and microphthalmia in zebrafish, and disruption of the apical junction of the retinal neural epithelium in mouse, mimicking the phenotype of Fz5/Fz8 compound conditional knockout mutants. Our studies have revealed a conserved role of Wnt-Frizzled (FZD) signaling in ocular development and directly implicate WNT-FZD signaling both in normal closure of the human optic fissure and pathogenesis of coloboma.

PMID:
26908622
PMCID:
PMC4787907
DOI:
10.1093/hmg/ddw020
[Indexed for MEDLINE]
Free PMC Article

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