A <i>Trans</i>-Acting Protein Effect Causes Severe Eye Malformation in the <i>Mp</i> Mouse

Rainger, Joe, Keighren, Margaret, Keene, Douglas R, Charbonneau, Noe L, Rainger, Jacqueline K, Fisher, Malcolm, Mella, Sebastien, Huang, Jeffrey T-J, Rose, Lorraine, van't Hof, Rob
et al (show 3 more authors) (2013) A <i>Trans</i>-Acting Protein Effect Causes Severe Eye Malformation in the <i>Mp</i> Mouse. PLOS GENETICS, 9 (12). e1003998-.

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Mp is an irradiation-induced mouse mutation associated with microphthalmia, micropinna and hind limb syndactyly. We show that Mp is caused by a 660 kb balanced inversion on chromosome 18 producing reciprocal 3-prime gene fusion events involving Fbn2 and Isoc1. The Isoc1-Fbn2 fusion gene (Isoc1(Mp)) mRNA has a frameshift and early stop codon resulting in nonsense mediated decay. Homozygous deletions of Isoc1 do not support a significant developmental role for this gene. The Fbn2-Isoc1 fusion gene (Fbn2 (Mp)) predicted protein consists of the N-terminal Fibrillin-2 (amino acids 1-2646, exons 1-62) lacking the C-terminal furin-cleavage site with a short out-of-frame extension encoded by the final exon of Isoc1. The Mp limb phenotype is consistent with that reported in Fbn2 null embryos. However, severe eye malformations, a defining feature of Mp, are not seen in Fbn2 null animals. Fibrillin-2(Mp) forms large fibrillar structures within the rough endoplasmic reticulum (rER) associated with an unfolded protein response and quantitative mass spectrometry shows a generalised defect in protein secretion in conditioned media from mutant cells. In the embryonic eye Fbn2 is expressed within the peripheral ciliary margin (CM). Mp embryos show reduced canonical Wnt-signalling in the CM - known to be essential for ciliary body development - and show subsequent aplasia of CM-derived structures. We propose that the Mp "worse-than-null" eye phenotype plausibly results from a failure in normal trafficking of proteins that are co-expressed with Fbn2 within the CM. The prediction of similar trans-acting protein effects will be an important challenge in the medical interpretation of human mutations from whole exome sequencing.

Item Type: Article
Uncontrolled Keywords: Eye, Chromosomes, Human, Pair 18, Animals, Humans, Mice, Syndactyly, Eye Abnormalities, Microphthalmos, Microfilament Proteins, Phenotype, Mutation, Frameshift Mutation, Exons, Chromosome Inversion, Wnt Signaling Pathway, Fibrillins, Fibrillin-2
Depositing User: Symplectic Admin
Date Deposited: 17 Dec 2018 16:42
Last Modified: 13 Oct 2023 00:59
DOI: 10.1371/journal.pgen.1003998
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3030175