title: A trans-acting protein effect causes severe eye malformation in the Mp mouse.
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.
authors.affiliation: The MRC Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Joe
authors.initials: J
authors.lastname: Rainger
authors.affiliation: The MRC Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Keighren
authors.affiliation: Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.affiliation: Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Noe L
authors.initials: NL
authors.lastname: Charbonneau
authors.affiliation: The MRC Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Rainger
authors.affiliation: The MRC Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Fisher
authors.affiliation: The MRC Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Mella
authors.affiliation: Biomarker and Drug Analysis Core Facility, Medical Research Institute, School of Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: Jeffrey T-J
authors.initials: JT
authors.lastname: Huang
authors.affiliation: Molecular Medicine Centre, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Rose
authors.affiliation: Molecular Medicine Centre, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Rob
authors.initials: R
authors.lastname: van't Hof
authors.affiliation: Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Lynne Y
authors.initials: LY
authors.lastname: Sakai
authors.affiliation: The MRC Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.affiliation: The MRC Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Fitzpatrick
mesh_terms: D000818:Animals; D007446:Chromosome Inversion / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D005091:Exons; D005123:Eye / Q000254:growth & development / Q000503:physiopathology; D005124:Eye Abnormalities / Q000235:genetics* / Q000503:physiopathology; D000071840:Fibrillin-2; D000071837:Fibrillins; D016368:Frameshift Mutation; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D008850:Microphthalmos / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000528:radiation effects*; D010641:Phenotype; D013576:Syndactyly / Q000235:genetics / Q000503:physiopathology; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C000605723:FBN2 protein, human; C000605728:Fbn2 protein, mouse; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins