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Human Molecular Genetics Advance Access originally published online on September 13, 2005
Human Molecular Genetics 2005 14(21):3161-3168; doi:10.1093/hmg/ddi348
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy

Tom Van Agtmael1,3,*, Ursula Schlötzer-Schrehardt4, Lisa McKie3, David G. Brownstein2, Angela W. Lee3, Sally H. Cross3, Yoshikazu Sado6, John J. Mullins1, Ernst Pöschl5 and Ian J. Jackson3

1Molecular Physiology, Centre for Cardiovascular Science and 2Division of Pathology, School of Molecular and Clinical Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK, 3Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, UK, 4Department of Ophthalmology and 5Department of Experimental Medicine I, University of Erlangen-Nürnberg, Germany and 6Shigei Medical Research Institute, Okayama, Japan

* To whom correspondence should be addressed at: Molecular Physiology, Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Email: tom.vanagtmael{at}ed.ac.uk

Received May 6, 2005; Revised July 4, 2005; Accepted September 8, 2005

Members of the type IV collagen family are essential components of all basement membranes (BMs) and define structural stability as well as tissue-specific functions. The major isoform, {alpha}1.{alpha}1.{alpha}2(IV), contributes to the formation of many BMs and its deficiency causes embryonic lethality in mouse. We have identified an allelic series of three ENU induced dominant mouse mutants with missense mutations in the gene Col4a1 encoding the {alpha}1(IV) subunit chain. Two severe alleles (Bru and Svc) have mutations affecting the conserved glycine residues in the Gly-Xaa-Yaa collagen repeat. Bru heterozygous mice display defects similar to Axenfeld–Rieger anomaly, including iris defects, corneal opacity, vacuolar cataracts, significant iris/corneal adhesions, buphthalmos and optic nerve cupping, a sign indicative of glaucoma. Kidneys of Bru mice have peripheral glomerulopathy characterized by hypertrophy and hyperplasia of the parietal epithelium of Bowman's capsule. A milder allele (Raw) contains a mutation in the Yaa residue of the collagen repeat and was identified by a silvery appearance of the retinal arterioles. All phenotypes are associated with BM defects that affect the eye, kidney and other tissues. This allelic series shows that mutations affecting the collagen domain cause dominant negative effects on the expression and function of the major collagen IV isoform {alpha}1(IV), and pathological effects vary with the individual mutations.


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