{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T10:46:48Z","timestamp":1792234008564,"version":"4.4.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2016,10,3]],"date-time":"2016-10-03T00:00:00Z","timestamp":1475452800000},"content-version":"vor","delay-in-days":1061,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Collagen type IV alpha 1 and 2 (COL4A1 and COL4A2) are present in nearly all basement membranes. COL4A1 and COL4A2 mutations are pleiotropic, affecting multiple organ systems to differing degrees, and both genetic-context and environmental factors influence this variable expressivity. Here, we report important phenotypic and molecular differences in an allelic series of Col4a1 and Col4a2 mutant mice that are on a uniform genetic background. We evaluated three organs commonly affected by COL4A1 and COL4A2 mutations and discovered allelic heterogeneity in the penetrance and severity of ocular dysgenesis, myopathy and brain malformations. Similarly, we show allelic heterogeneity in COL4A1 and COL4A2 biosynthesis. While most mutations that we examined caused increased intracellular and decreased extracellular COL4A1 and COL4A2, we identified three mutations with distinct biosynthetic signatures. Reduced temperature or presence of 4-phenylbutyrate ameliorated biosynthetic defects in primary cell lines derived from mutant mice. Together, our data demonstrate the effects and clinical implications of allelic heterogeneity in Col4a1- and Col4a2-related diseases. Understanding allelic differences will be valuable for increasing prognostic accuracy and for the development of therapeutic interventions that consider the nature of the molecular cause in patients with COL4A1 and COL4A2 mutations.<\/jats:p>","DOI":"10.1093\/hmg\/ddt560","type":"journal-article","created":{"date-parts":[[2013,11,8]],"date-time":"2013-11-08T02:41:42Z","timestamp":1383878502000},"page":"1709-1722","source":"Crossref","is-referenced-by-count":86,"title":["Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused by <i>Col4a1 and Col4a2<\/i> mutations"],"prefix":"10.1093","volume":"23","author":[{"given":"Debbie S.","family":"Kuo","sequence":"first","affiliation":[{"name":"1 \u00a0Department of Ophthalmology and"},{"name":"2 \u00a0Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandre","family":"Labelle-Dumais","sequence":"additional","affiliation":[{"name":"1 \u00a0Department of Ophthalmology and"},{"name":"2 \u00a0Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Mao","sequence":"additional","affiliation":[{"name":"1 \u00a0Department of Ophthalmology and"},{"name":"2 \u00a0Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Jeanne","sequence":"additional","affiliation":[{"name":"1 \u00a0Department of Ophthalmology and"},{"name":"2 \u00a0Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"Kauffman","sequence":"additional","affiliation":[{"name":"1 \u00a0Department of Ophthalmology and"},{"name":"2 \u00a0Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Allen","sequence":"additional","affiliation":[{"name":"1 \u00a0Department of Ophthalmology and"},{"name":"2 \u00a0Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Favor","sequence":"additional","affiliation":[{"name":"3 \u00a0Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg D-85764, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas B.","family":"Gould","sequence":"additional","affiliation":[{"name":"1 \u00a0Department of Ophthalmology and"},{"name":"2 \u00a0Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,11,7]]},"reference":[{"key":"2022050522032577700_DDT560C1","doi-asserted-by":"crossref","first-page":"30716","DOI":"10.1074\/jbc.M004569200","article-title":"Type IV collagen of the glomerular basement membrane. Evidence that the chain specificity of network assembly is encoded by the noncollagenous NC1 domains","volume":"275","author":"Boutaud","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2022050522032577700_DDT560C2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/jemt.20564","article-title":"Mammalian collagen IV","volume":"71","author":"Khoshnoodi","year":"2008","journal-title":"Microsc. Res. Tech."},{"key":"2022050522032577700_DDT560C3","doi-asserted-by":"crossref","first-page":"R97","DOI":"10.1093\/hmg\/dds346","article-title":"COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets","volume":"21","author":"Kuo","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2022050522032577700_DDT560C4","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1055\/s-0032-1325116","article-title":"COL4A1-related disease: raised creatine kinase and cerebral calcification as useful pointers","volume":"43","author":"Tonduti","year":"2012","journal-title":"Neuropediatrics"},{"key":"2022050522032577700_DDT560C5","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/hmg\/dds436","article-title":"Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency","volume":"22","author":"Lemmens","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"2022050522032577700_DDT560C6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/ana.23736","article-title":"Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly","volume":"73","author":"Yoneda","year":"2013","journal-title":"Ann. Neurol."},{"key":"2022050522032577700_DDT560C7","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1056\/NEJMoa053727","article-title":"Role of COL4A1 in small-vessel disease and hemorrhagic stroke","volume":"354","author":"Gould","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"2022050522032577700_DDT560C8","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1093\/hmg\/ddm024","article-title":"Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis","volume":"16","author":"Gould","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2022050522032577700_DDT560C9","doi-asserted-by":"crossref","first-page":"e1002062","DOI":"10.1371\/journal.pgen.1002062","article-title":"COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans","volume":"7","author":"Labelle-Dumais","year":"2011","journal-title":"PLoS Genet."},{"key":"2022050522032577700_DDT560C10","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1056\/NEJMoa071906","article-title":"COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps","volume":"357","author":"Plaisier","year":"2007","journal-title":"N. Engl. J. 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Genet."},{"key":"2022050522032577700_DDT560C14","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.brainres.2011.03.026","article-title":"Neocortical molecular layer heterotopia in substrains of C57BL\/6 and C57BL\/10 mice","volume":"1391","author":"Lipoff","year":"2011","journal-title":"Brain Res."},{"key":"2022050522032577700_DDT560C15","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1002\/ajmg.a.33659","article-title":"Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain","volume":"152A","author":"Plaisier","year":"2010","journal-title":"Am. J. Med. Genet. 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Sci."},{"key":"2022050522032577700_DDT560C25","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1126\/science.1109418","article-title":"Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly","volume":"308","author":"Gould","year":"2005","journal-title":"Science"},{"key":"2022050522032577700_DDT560C26","doi-asserted-by":"crossref","first-page":"35872","DOI":"10.1074\/jbc.M109.060384","article-title":"Abnormal expression of collagen IV in lens activates unfolded protein response resulting in cataract","volume":"284","author":"Firtina","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2022050522032577700_DDT560C27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ajhg.2011.11.022","article-title":"COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke","volume":"90","author":"Jeanne","year":"2012","journal-title":"Am. J. Hum. 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Cell Biol."},{"key":"2022050522032577700_DDT560C31","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1093\/hmg\/ddh284","article-title":"Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities","volume":"13","author":"Zenker","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2022050522032577700_DDT560C32","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ydbio.2006.07.005","article-title":"Mutations in laminin alpha 1 result in complex, lens-independent ocular phenotypes in zebrafish","volume":"299","author":"Semina","year":"2006","journal-title":"Dev. Biol."},{"key":"2022050522032577700_DDT560C33","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/ajmg.a.31564","article-title":"Neurodevelopmental deficits in Pierson (microcoria-congenital nephrosis) syndrome","volume":"143","author":"W\u00fchl","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"2022050522032577700_DDT560C34","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.ajo.2008.05.039","article-title":"Ophthalmological aspects of Pierson syndrome","volume":"146","author":"Bredrup","year":"2008","journal-title":"Am. J. Ophthalmol."},{"key":"2022050522032577700_DDT560C35","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/humu.21304","article-title":"Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum","volume":"31","author":"Matejas","year":"2010","journal-title":"Hum. Mutat."},{"key":"2022050522032577700_DDT560C36","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/ng.836","article-title":"Recessive LAMC3 mutations cause malformations of occipital cortical development","volume":"43","author":"Barak","year":"2011","journal-title":"Nat. Genet."},{"key":"2022050522032577700_DDT560C37","doi-asserted-by":"crossref","first-page":"e43794","DOI":"10.1371\/journal.pone.0043794","article-title":"A splice site mutation in laminin-\u03b12 results in a severe muscular dystrophy and growth abnormalities in zebrafish","volume":"7","author":"Gupta","year":"2012","journal-title":"PloS ONE"},{"key":"2022050522032577700_DDT560C38","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/dneu.22057","article-title":"\u03b22 and \u03b33 laminins are critical cortical basement membrane components: ablation of Lamb2 and Lamc3 genes disrupts cortical lamination and produces dysplasia","volume":"73","author":"Radner","year":"2013","journal-title":"Dev. 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Cortex"},{"key":"2022050522032577700_DDT560C42","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/nature00838","article-title":"Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy","volume":"418","author":"Moore","year":"2002","journal-title":"Nature"},{"key":"2022050522032577700_DDT560C43","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1534\/genetics.106.064733","article-title":"Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles","volume":"175","author":"Favor","year":"2007","journal-title":"Genetics"},{"key":"2022050522032577700_DDT560C44","first-page":"71","article-title":"Embryo-derived stem cell lines","volume-title":"Teratocarcinomas and Embryonic Stem Cells: A Practical Approach","author":"Robertson","year":"1987"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/23\/7\/1709\/43557380\/hmg_23_7_1709.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/23\/7\/1709\/43557380\/hmg_23_7_1709.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T22:04:11Z","timestamp":1651788251000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/23\/7\/1709\/653133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11,7]]},"references-count":44,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2013,11,7]]},"published-print":{"date-parts":[[2014,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddt560","relation":{},"ISSN":["1460-2083","0964-6906"],"issn-type":[{"value":"1460-2083","type":"electronic"},{"value":"0964-6906","type":"print"}],"subject":[],"published-other":{"date-parts":[[2014,4,1]]},"published":{"date-parts":[[2013,11,7]]}}}