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Human Molecular Genetics Advance Access originally published online on August 27, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 20 2657-2667
DOI: 10.1093/hmg/ddg289
© 2003 Oxford University Press

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

Caroline Hayward1,{dagger}, Xinhua Shu1,{dagger}, Artur V. Cideciyan2, Alan Lennon1, Perdita Barran3, Sepideh Zareparsi4, Lindsay Sawyer5, Grace Hendry1, Baljean Dhillon6, Ann H. Milam2, Philip J. Luthert7, Anand Swaroop4, Nicholas D. Hastie1, Samuel G. Jacobson2 and Alan F. Wright1,*

1MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK, 2Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 3School of Chemistry, University of Edinburgh, Edinburgh, UK, 4Departments of Ophthalmology and Visual Sciences, and Human Genetics, University of Michigan, Ann Arbor, MI, USA, 5Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh, UK, 6Department of Ophthalmology, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK and 7Department of Pathology, Institute of Ophthalmology, University College London, London, UK

Received June 17, 2003; Accepted August 15, 2003

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.

* To whom correspondence should be addressed. Tel: +44 1314678437; Fax: +44 1314678456; Email: alan.wright{at}hgu.mrc.ac.uk

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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