A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies

Marco Castori, Enza Maria Valente, Maurizio Clementi, Alma Patrizia Tormene, Francesco Brancati, Viviana Caputo, Bruno Dallapiccola

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Abstract

PURPOSE. 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.

Original languageEnglish
Pages (from-to)3539-3544
Number of pages6
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number10
DOIs
Publication statusPublished - Oct 2005

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Retinal Dystrophies
Multigene Family
Lod Score
Mutation
Chromosomes, Human, Pair 6
Chromosome Mapping
Genome
Electrooculography
Penetrance
Genetic Recombination
Genes
Visual Acuity
Cone-Rod Dystrophies

ASJC Scopus subject areas

  • Ophthalmology

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A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies. / Castori, Marco; Valente, Enza Maria; Clementi, Maurizio; Tormene, Alma Patrizia; Brancati, Francesco; Caputo, Viviana; Dallapiccola, Bruno.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 10, 10.2005, p. 3539-3544.

Research output: Contribution to journalArticle

Castori, Marco ; Valente, Enza Maria ; Clementi, Maurizio ; Tormene, Alma Patrizia ; Brancati, Francesco ; Caputo, Viviana ; Dallapiccola, Bruno. / A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies. In: Investigative Ophthalmology and Visual Science. 2005 ; Vol. 46, No. 10. pp. 3539-3544.
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AU - Brancati, Francesco

AU - Caputo, Viviana

AU - Dallapiccola, Bruno

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N2 - PURPOSE. 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.

AB - PURPOSE. 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.

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