A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies.
OBJECTIVE
To characterize clinically and genetically a four-generation Italian family with autosomal dominant retinal dystrophy.


METHODS
Thirty-seven family members underwent a detailed ophthalmologic investigation, comprising visual acuity determination, fundoscopy, electroretinogram, and electrooculogram. A genome-wide scan was performed, and three candidate genes mapping to the linked region were screened for mutations by direct sequencing.


RESULTS
Nineteen individuals were affected by cone-rod dystrophy and four by cone dystrophy, whereas, in another subject, the diagnosis was compatible with central areolar choroidal dystrophy. The genome-wide search allowed mapping the disease locus to chromosome 6, region p12.2-p21.1, with a maximum lod score of 6.71. Analysis of key recombinants in affected individuals placed the locus to a 12-Mb region flanked by newly generated markers 6-41025 and 6-52969. Assuming complete penetrance, recombinations in two healthy individuals defined a smaller critical region of 3.7 Mb between markers 6-42153 and D6S459. Three genes mapping within the linked interval (RDS, GUCA1A, and GUCA1B) were considered excellent candidates because of their involvement in distinct forms of retinal dystrophies. However, mutation analyses of these genes failed to identify pathogenetic mutations.


CONCLUSIONS
The significant lod scores obtained and the absence of mutations in RDS, GUCA1A, and GUCA1B support the existence of a novel, yet unidentified gene responsible for retinal dystrophy within the chromosome 6 cluster.
Castori
Marco
M
Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza (IRCCS CSS), Mendel Institute, Rome, Italy.
Valente
Enza Maria
EM
Clementi
Maurizio
M
Tormene
Alma Patrizia
AP
Brancati
Francesco
F
Caputo
Viviana
V
Dallapiccola
Bruno
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004585:Electrooculography; D004596:Electroretinography; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D051604:Guanylate Cyclase-Activating Proteins / Q000235:genetics; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D008126:Lod Score; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D064531:Peripherins; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics*; D014792:Visual Acuity
C496736:GUCA1A protein, human; C496739:GUCA1B protein, human; D051604:Guanylate Cyclase-Activating Proteins; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C578997:PRPH2 protein, human; D064531:Peripherins