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A trans-acting protein effect causes severe eye malformation in the Mp mouse.
- Source :
-
PLoS genetics [PLoS Genet] 2013; Vol. 9 (12), pp. e1003998. Date of Electronic Publication: 2013 Dec 12. - Publication Year :
- 2013
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Abstract
- 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.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Chromosome Inversion genetics
Chromosomes, Human, Pair 18 genetics
Exons
Eye growth & development
Eye physiopathology
Eye Abnormalities physiopathology
Fibrillin-2
Fibrillins
Frameshift Mutation
Humans
Mice
Microphthalmos physiopathology
Phenotype
Syndactyly genetics
Syndactyly physiopathology
Wnt Signaling Pathway genetics
Eye Abnormalities genetics
Microfilament Proteins genetics
Microphthalmos genetics
Mutation radiation effects
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 9
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 24348270
- Full Text :
- https://doi.org/10.1371/journal.pgen.1003998