Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation.
OBJECTIVE
To identify the gene responsible for a complex ocular phenotype of late-onset macular degeneration, long anterior zonules (LAZ), and elevated intraocular pressure (IOP) and to study its expression.


METHODS
Ocular examination, visual field, fluorescein angiography, and electrophysiology testing were performed. One affected individual was treated with vitamin A. DNA from 55 family members (UM:H389) was used for linkage, mapping, and mutation analysis. Linkage analysis of macular degeneration and LAZ phenotypes was performed independently. Mutations in candidate genes were screened by sequencing. mRNA expression of CTRP5 and MFRP, which are bicistronic genes, was studied by semiquantitative RT-PCR (qRT-PCR) in various human tissues. CTRP5 expression was also evaluated by in situ hybridization.


RESULTS
Affected members had LAZ detectable by the third decade and/or macular degeneration by the fourth to fifth decade. A six-month treatment with vitamin A shortened dark adaptation considerably in one affected member. Both conditions mapped independently with zero recombination to 11q23, with maximum lod scores of 3.31 for macular degeneration and 5.41 for LAZ. The same CTRP5 missense mutation was identified in all affected individuals. Retinal pigment epithelium (RPE) and ciliary epithelium (CE) showed highest CTRP5 transcript expression, which was also true for MFRP. CTRP5 tissue expression was confirmed by in situ hybridization.


CONCLUSIONS
A single locus at 11q23 is implicated in a complex ocular phenotype involving RPE and CE, tissues of neuroectodermal origin. All individuals with either LAZ and/or macular degeneration carry the same CTRP5 S163R mutation, which is transmitted in autosomal dominant manner.
Ayyagari
Radha
R
Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA. ayyagari@umich.edu
Mandal
Md Nawajes A
MN
Karoukis
Athanasios J
AJ
Chen
Lianchun
L
McLaren
Ning C
NC
Lichter
Mona
M
Wong
David T
DT
Hitchcock
Peter F
PF
Caruso
Rafael C
RC
Moroi
Sayoko E
SE
Maumenee
Irene H
IH
Sieving
Paul A
PA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007498:Iris / Q000378:metabolism; D007905:Lens Diseases / Q000235:genetics* / Q000378:metabolism; D007908:Lens, Crystalline / Q000473:pathology*; D008022:Ligaments / Q000473:pathology*; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014801:Vitamin A / Q000008:administration & dosage; D000099274:Frizzled-Related Proteins
D003094:Collagen; D008565:Membrane Proteins; D012333:RNA, Messenger; D014801:Vitamin A; C487851:C1QTNF5 protein, human; C490110:MFRP protein, human; D000099274:Frizzled-Related Proteins