Late-onset autosomal dominant macular dystrophy with choroidal neovascularization and nonexudative maculopathy associated with mutation in the RDS gene.
OBJECTIVE
To examine the molecular genetic basis and phenotypic characteristics of an unusual late-onset autosomal dominant macular dystrophy with features of age-related macular degeneration (AMD) in a large family (SUNY901), by using linkage and mutation analyses.


METHODS
Blood samples were collected from 17 affected members, 17 clinically unaffected members, and 5 unrelated spouses. Clinical analyses included a review of medical history and standard ophthalmic examination with fundus photography, fluorescein angiography, and electroretinography. Linkage and haplotype analyses were performed with microsatellite markers. Mutation analysis was performed by amplification of exons followed by sequencing.


RESULTS
A wide spectrum of clinical phenotypes including exudative and nonexudative maculopathy was observed, with onset in the late fifth decade. Linkage analysis excluded most of the previously known maculopathy loci. Markers D6S1604 (Z(max) of 3.18 at theta = 0), and D6S282 (Z(max) of 3.18 at theta = 0) gave significant positive LOD scores and haplotype analysis localized the disease gene to a 9-centimorgan (cM) interval between markers D6S1616 and D6S459. Mutation analysis excluded the GUCA1A and GUCA1B genes and revealed a missense mutation in the RDS/peripherin gene leading to a Tyr141Cys substitution. A phenotype and haplotype comparison between this and a separate family with the Tyr141Cys mutation suggested the presence of a common ancestral haplotype.


CONCLUSIONS
The RDS mutation in codon 141 is associated with an unusual AMD-like late-onset maculopathy. An apparent selective bias was noted favoring the transmission of the mutant allele. These observations broaden the spectrum of phenotypes associated with RDS gene mutations.
Khani
Shahrokh C
SC
Department of Ophthalmology, State University of New York at Buffalo, Buffalo, New York, USA.
Karoukis
Athanasios J
AJ
Young
Joyce E
JE
Ambasudhan
Rajesh
R
Burch
Tracy
T
Stockton
Richard
R
Lewis
Richard Alan
RA
Sullivan
Lori S
LS
Daiger
Stephen P
SP
Reichel
Elias
E
Ayyagari
Radha
R
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005122:Exudates and Transudates; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D005799:Genes, Dominant; D006239:Haplotypes; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins; D018895:Microsatellite Repeats; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D064531:Peripherins; D010641:Phenotype
D005136:Eye Proteins; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C578994:PRPH protein, human; C578997:PRPH2 protein, human; D064531:Peripherins