title: Connexin46fs380 causes progressive cataracts.
abstract: OBJECTIVE
  Although many connexin46 (Cx46) mutants have been linked to inherited human cataracts, there are no adequate animal models for their study. The current experiments were designed to characterize the consequences of expression of one such mutant, Cx46fs380, in the mouse lens.
  
  
  METHODS
  Mice expressing Cx46fs380 were generated by a knockin strategy. Levels and distribution of specific proteins were analyzed by immunoblotting and immunofluorescence.
  
  
  RESULTS
  Dark-field microscopy revealed that lenses of young heterozygous and homozygous Cx46fs380 mice did not have opacities, but they developed anterior nuclear cataracts that became more severe with age. Immunofluorescence and immunoblotting showed that Cx46 was severely reduced in both heterozygous and homozygous Cx46fs380 lenses at 1 month of age, whereas immunoreactive connexin50 (Cx50) was moderately decreased. The reduction in Cx50 became more severe in older lenses. The solubilities of crystallins from young wild-type and fs380 mice were similar, but older fs380 lenses exhibited abnormalities of abundance, solubility, and modification of some crystallins.
  
  
  CONCLUSIONS
  Major decreases in connexin levels precede the development of cataracts. These mice represent a useful model for elucidation of the progression of lens abnormalities during cataractogenesis especially as caused by a mutant connexin.
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, United States.
authors.forename: Viviana M
authors.initials: VM
authors.lastname: Berthoud
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Minogue
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, United States.
authors.forename: Helena
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, United States.
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Snabb
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, United States.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Beyer
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D002386:Cataract / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017630:Connexins / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010784:Photomicrography; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017630:Connexins; C082917:GJA3 protein, human; D004247:DNA
keywords: cataract; connexin; crystallins; gap junction
references.citation: Hum Mol Genet. 2010 Dec 15;19(24):4759-73
references.pmid: 20858605
references.citation: Invest Ophthalmol Vis Sci. 2001 Mar;42(3):727-34
references.pmid: 11222534
references.citation: FEBS Lett. 2014 Apr 17;588(8):1297-303
references.pmid: 24434541
references.citation: Bull World Health Organ. 2004 Nov;82(11):844-51
references.pmid: 15640920
references.citation: Invest Ophthalmol Vis Sci. 2013 Nov 19;54(12):7614-22
references.pmid: 24204043
references.citation: J Cell Biol. 1989 Feb;108(2):595-605
references.pmid: 2537319
references.citation: Exp Eye Res. 2007 Mar;84(3):513-28
references.pmid: 17217947
references.citation: Am J Hum Genet. 1999 May;64(5):1357-64
references.pmid: 10205266
references.citation: Philos Trans R Soc Lond B Biol Sci. 2011 Apr 27;366(1568):1234-49
references.pmid: 21402583
references.citation: J Biol Chem. 2005 Dec 9;280(49):40788-95
references.pmid: 16204255
references.citation: J Biol Chem. 2001 Aug 3;276(31):28999-9006
references.pmid: 11395508
references.citation: Anat Embryol (Berl). 2004 Nov;209(1):11-8
references.pmid: 15455226
references.citation: PLoS One. 2012;7(12):e52894
references.pmid: 23300808
references.citation: Jpn J Ophthalmol. 1987;31(3):433-9
references.pmid: 3430859
references.citation: Prog Biophys Mol Biol. 2014 Jul;115(1):21-31
references.pmid: 24613629
references.citation: Proteomics Clin Appl. 2014 Apr;8(3-4):195-203
references.pmid: 24458544
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15303-8
references.pmid: 9860964
references.citation: Mol Biol Cell. 2011 Dec;22(24):4776-86
references.pmid: 22031297
references.citation: Invest Ophthalmol Vis Sci. 2004 Sep;45(9):3196-202
references.pmid: 15326140
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10449-53
references.pmid: 1438232
references.citation: Exp Eye Res. 2006 Sep;83(3):688-96
references.pmid: 16696970
references.citation: J Cell Biol. 1991 Nov;115(4):1077-89
references.pmid: 1659572
references.citation: Exp Eye Res. 2012 Sep;102:28-37
references.pmid: 22713599
references.citation: Physiol Rev. 2010 Jan;90(1):179-206
references.pmid: 20086076
references.citation: J Cell Biol. 1997 May 19;137(4):847-57
references.pmid: 9151687
references.citation: Eur J Cell Biol. 2006 Aug;85(8):729-52
references.pmid: 16740340
references.citation: Hum Mol Genet. 2011 Jan 1;20(1):28-39
references.pmid: 20926451
references.citation: Exp Eye Res. 2001 Dec;73(6):867-76
references.pmid: 11846517
references.citation: Front Pharmacol. 2013 Apr 15;4:43
references.pmid: 23596416
references.citation: Cell. 1997 Dec 12;91(6):833-43
references.pmid: 9413992
references.citation: Development. 2006 May;133(10):2033-40
references.pmid: 16611690
references.citation: Hum Mol Genet. 2008 Feb 15;17(4):539-54
references.pmid: 18003637
references.citation: J Cell Biol. 1998 Nov 2;143(3):815-25
references.pmid: 9813099
references.citation: Br J Ophthalmol. 2012 May;96(5):614-8
references.pmid: 22133988
references.citation: Development. 2002 Jan;129(1):167-74
references.pmid: 11782410
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20512-6
references.pmid: 18077386
references.citation: Am J Physiol Cell Physiol. 2000 Sep;279(3):C596-602
references.pmid: 10942709
references.citation: Trends Mol Med. 2012 May;18(5):273-82
references.pmid: 22520268
references.citation: Dev Genet. 1999;24(1-2):27-32
references.pmid: 10079508
references.citation: Invest Ophthalmol Vis Sci. 2009 Dec;50(12):5837-45
references.pmid: 19684000
references.citation: Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2685-94
references.pmid: 17525200
references.citation: Br J Ophthalmol. 2014 May;98(5):629-38
references.pmid: 24665132
references.citation: Mol Vis. 2010 Oct 08;16:2007-15
references.pmid: 21042563
references.citation: Invest Ophthalmol Vis Sci. 2004 Mar;45(3):884-91
references.pmid: 14985306
references.citation: Mol Vis. 2007 Sep 14;13:1680-94
references.pmid: 17893670
references.citation: Biochim Biophys Acta. 2009 Oct;1790(10):1095-108
references.pmid: 19463898
references.citation: Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1287-91
references.pmid: 8577756
references.citation: Semin Cell Biol. 1992 Feb;3(1):49-58
references.pmid: 1320431
references.citation: Invest Ophthalmol Vis Sci. 2011 Feb 22;52(2):882-9
references.pmid: 20861491