Human Molecular Genetics Advance Access published online on August 27, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg289
© 2003 by Oxford University Press
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1 MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK
* To whom correspondence should be addressed. E-mail: alan.wright{at}hgu.mrc.ac.uk.
A primary feature of age-related macular degeneration (AMD) is the presence of extracellular deposits between the retinal pigment epithelium (RPE) and underlying Bruch's membrane, leading to RPE dysfunction, photoreceptor death and severe visual loss. AMD accounts for about 50% of blind registrations in western countries and is a common, genetically complex disorder. Very little is known regarding its molecular basis. Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder with striking clinical and pathological similarity to AMD. Here we show that L-ORD is genetically heterogeneous and that a proposed founder mutation in the CTRP5 (C1QTNF5) gene, which encodes a novel short-chain collagen, changes a highly conserved serine to arginine (Ser163Arg) in 7/14 L-ORD families and 0/1000 control individuals. The mutation occurs in the gC1q domain of CTRP5 and results in abnormal high molecular weight aggregate formation which may alter its higher-order structure and interactions. These results indicate a novel disease mechanism involving abnormal adhesion between RPE and Bruch's membrane.
Article
Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration - a genetic model for age-related macular degeneration
2 Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, USA
3 School of Chemistry, University of Edinburgh, Edinburgh, UK
4 Departments of Ophthalmology and Visual Sciences, and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
5 Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh, UK
6 Department of Ophthalmology, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK
7 Department of Pathology, Institute of Ophthalmology, University College London, London, UK
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