A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma
| Autor: | Andrew J. Waskiewicz, Joe Rainger, Souparnika H. Manjunath, Ramakrishna P. Alur, Christina Gerth-Kahlert, Erin Strachan, Sonya A. Widen, Anand Swaroop, Rinki Ratnapriya, Tiansen Li, Brian P. Brooks, James A B Floyd, Kathleen A. Williamson, Chunqiao Liu, Ordan J. Lehmann, Archana Balakrishnan, David R. FitzPatrick |
|---|---|
| Přispěvatelé: | University of Zurich, Swaroop, Anand |
| Rok vydání: | 2016 |
| Předmět: |
10018 Ophthalmology Clinic
Male 0301 basic medicine 2716 Genetics (clinical) congenital hereditary and neonatal diseases and abnormalities Frizzled DNA Mutational Analysis 610 Medicine & health Biology medicine.disease_cause Microphthalmia Frameshift mutation Mice 03 medical and health sciences 1311 Genetics Mutant protein 1312 Molecular Biology Genetics medicine Animals Humans Microphthalmos Eye Abnormalities Frameshift Mutation Wnt Signaling Pathway Molecular Biology Zebrafish Genetics (clinical) Coloboma Mutation Wnt signaling pathway Articles General Medicine medicine.disease Molecular biology Frizzled Receptors eye diseases Pedigree Transmembrane domain 030104 developmental biology Female sense organs |
| Zdroj: | Liu, C, Widen, S, Williamson, K, Ratnapriya, R, Gerth-Kahlert, C, Rainger, J, Alur, R, Strachan, E, Manjanath, S, Balakrishnan, A, Floyd, J, Li, T, Waskiewicz, A, Brooks, B, Lehmann, O J & FitzPatrick, D & Swaroop, A 2016, ' A Secreted WNT-Ligand Binding Domain of FZD5 Generated by a Frameshift Mutation Causes Autosomal Dominant Coloboma ', Human Molecular Genetics . https://doi.org/10.1093/hmg/ddw020 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|