title: Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.
abstract: Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1(+/Δex41)mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes.
authors.affiliation: Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143.
authors.forename: Marcel V
authors.initials: MV
authors.lastname: Alavi
authors.affiliation: Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Pawlikowski
authors.affiliation: Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143.
authors.forename: Manana
authors.initials: M
authors.lastname: Kvezereli
authors.affiliation: Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143.
authors.forename: Jacque L
authors.initials: JL
authors.lastname: Duncan
authors.affiliation: Department of Ophthalmology, University of Rochester, Rochester, NY, 14642.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.affiliation: Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, ME 04609.
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.affiliation: Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143.|Department of Anatomy and Institute for Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
mesh_terms: D000818:Animals; D024141:Collagen Type IV / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019721:Ophthalmoscopes; D010641:Phenotype; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012164:Retinal Diseases / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D041623:Tomography, Optical Coherence
chemical_list: D024141:Collagen Type IV
references.citation: Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1621-7
references.pmid: 19850830
references.citation: Ophthalmologica. 1990;200(1):39-44
references.pmid: 2181360
references.citation: Science. 2005 May 20;308(5725):1167-71
references.pmid: 15905400
references.citation: PLoS Genet. 2011 May;7(5):e1002062
references.pmid: 21625620
references.citation: N Engl J Med. 2007 Dec 27;357(26):2687-95
references.pmid: 18160688
references.citation: Nat Med. 2001 May;7(5):575-83
references.pmid: 11329059
references.citation: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3578-85
references.pmid: 12882810
references.citation: Am J Pathol. 2012 May;180(5):1917-27
references.pmid: 22429967
references.citation: Genetics. 2007 Feb;175(2):725-36
references.pmid: 17179069
references.citation: Circulation. 2015 May 5;131(18):1555-65
references.pmid: 25753534
references.citation: Invest Ophthalmol Vis Sci. 2015 Oct;56(11):6823-31
references.pmid: 26567795
references.citation: Curr Opin Neurol. 2011 Feb;24(1):63-8
references.pmid: 21157337
references.citation: Circ Res. 2003 Oct 3;93(7):664-73
references.pmid: 12958144
references.citation: Hum Mol Genet. 2007 Apr 1;16(7):798-807
references.pmid: 17317786
references.citation: Dev Cell. 2009 Oct;17(4):482-93
references.pmid: 19853562
references.citation: Graefes Arch Clin Exp Ophthalmol. 2014 Nov;252(11):1789-94
references.pmid: 25228067
references.citation: Dev Med Child Neurol. 2012 Jun;54(6):569-74
references.pmid: 22574627
references.citation: Anal Biochem. 2010 Apr 15;399(2):211-7
references.pmid: 20036209
references.citation: Hum Mol Genet. 2012 Oct 15;21(R1):R97-110
references.pmid: 22914737
references.citation: Circ Res. 2003 Nov 28;93(11):1074-81
references.pmid: 14576200
references.citation: Retina. 2009 Jun;29(6):732-9
references.pmid: 19516115
references.citation: Curr Top Membr. 2015;76:61-116
references.pmid: 26610912
references.citation: J Pathol. 2009 Dec;219(4):446-54
references.pmid: 19768732
references.citation: Eye (Lond). 2015 Jan;29(1):1-14
references.pmid: 25323851
references.citation: Retina. 2008 Feb;28(2):201-11
references.pmid: 18301024
references.citation: Invest Ophthalmol Vis Sci. 2011 Mar;52(3):1378-83
references.pmid: 21212186
references.citation: J Mol Med (Berl). 2013 Mar;91(3):311-21
references.pmid: 23329331
references.citation: Nat Rev Nephrol. 2013 Mar;9(3):170-8
references.pmid: 23165304
references.citation: Am J Pathol. 1996 Jun;148(6):1985-97
references.pmid: 8669483
references.citation: Hum Mol Genet. 2014 Apr 1;23(7):1709-22
references.pmid: 24203695
references.citation: PLoS One. 2014;9(9):e106507
references.pmid: 25188381
references.citation: Invest Ophthalmol Vis Sci. 2014 Jun;55(6):3709-19
references.pmid: 24845632
references.citation: J Cell Biol. 2006 Jan 2;172(1):151-62
references.pmid: 16391003
references.citation: N Engl J Med. 2006 Apr 6;354(14):1489-96
references.pmid: 16598045
references.citation: Histochem Cell Biol. 1995 Oct;104(4):267-75
references.pmid: 8548560
references.citation: Hum Mol Genet. 2005 Nov 1;14(21):3161-8
references.pmid: 16159887
references.citation: J Clin Invest. 2005 Oct;115(10):2801-10
references.pmid: 16151532
references.citation: Retina. 2001;21(5):416-34
references.pmid: 11642370
references.citation: Invest Ophthalmol Vis Sci. 2008 Jan;49(1):407-15
references.pmid: 18172119
references.citation: J Biol Chem. 2007 Nov 23;282(47):34420-8
references.pmid: 17890782
references.citation: Invest Ophthalmol Vis Sci. 2003 Feb;44(2):839-47
references.pmid: 12556420
references.citation: Matrix Biol. 2009 May;28(4):194-201
references.pmid: 19275937
references.citation: J Cell Biol. 1986 Dec;103(6 Pt 1):2467-73
references.pmid: 3782304
references.citation: J Biol Chem. 2006 Dec 15;281(50):38117-21
references.pmid: 17082192
references.citation: Arch Ophthalmol. 2007 Jun;125(6):795-803
references.pmid: 17562991
references.citation: Science. 1983 Sep 23;221(4617):1283-5
references.pmid: 6612342
references.citation: Ophthalmology. 1996 Dec;103(12):2042-53
references.pmid: 9003338
references.citation: PLoS One. 2010;5(7):e11676
references.pmid: 20652025
references.citation: Cell. 2009 Oct 16;139(2):285-98
references.pmid: 19837032
references.citation: Retina. 2011 Sep;31(8):1609-19
references.pmid: 21844839
references.citation: PLoS One. 2011;6(3):e17462
references.pmid: 21408222
references.citation: Retina. 2015 Mar;35(3):537-46
references.pmid: 25170864
references.citation: J Proteome Res. 2014 Jul 17;:null
references.pmid: 24990792
references.citation: Br J Ophthalmol. 2003 Feb;87(2):212-5
references.pmid: 12543754