A Trans-Acting Protein Effect Causes Severe Eye Malformation in the Mp Mouse

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 (isoc1mp) 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 (fbn2mp) 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-2mp 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. © 2013 rainger et al.