title: 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.
abstract: 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.
authors.affiliation: MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Xinhua
authors.initials: X
authors.lastname: Shu
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Alan
authors.initials: A
authors.lastname: Lennon
authors.forename: Perdita
authors.initials: P
authors.lastname: Barran
authors.forename: Sepideh
authors.initials: S
authors.lastname: Zareparsi
authors.forename: Lindsay
authors.initials: L
authors.lastname: Sawyer
authors.forename: Grace
authors.initials: G
authors.lastname: Hendry
authors.forename: Baljean
authors.initials: B
authors.lastname: Dhillon
authors.forename: Ann H
authors.initials: AH
authors.lastname: Milam
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Luthert
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000595:Amino Acid Sequence; D015153:Blotting, Western; D002874:Chromosome Mapping; D003094:Collagen / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013997:Time Factors
chemical_list: C487851:C1QTNF5 protein, human; D005819:Genetic Markers; D003094:Collagen