A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice

Choroideremia (CHM) is a rare X-linked disease leading to progressive retinal degeneration resulting in blindness. The disorder is caused by mutations in the CHM gene encoding REP-1 protein, an essential component of the Rab geranylgeranyltransferase (GGTase) complex. In the present study, we evalua...

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Published in:PloS one Vol. 11; no. 4; p. e0151943
Main Authors: Sanchez-Alcudia, Rocio, Garcia-Hoyos, Maria, Lopez-Martinez, Miguel Angel, Sanchez-Bolivar, Noelia, Zurita, Olga, Gimenez, Ascension, Villaverde, Cristina, Rodrigues-Jacy da Silva, Luciana, Corton, Marta, Perez-Carro, Raquel, Torriano, Simona, Kalatzis, Vasiliki, Rivolta, Carlo, Avila-Fernandez, Almudena, Lorda, Isabel, Trujillo-Tiebas, Maria J, Garcia-Sandoval, Blanca, Lopez-Molina, Maria Isabel, Blanco-Kelly, Fiona, Riveiro-Alvarez, Rosa, Ayuso, Carmen
Format: Journal Article
Language:English
Published: United States Public Library of Science 12-04-2016
Public Library of Science (PLoS)
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Summary:Choroideremia (CHM) is a rare X-linked disease leading to progressive retinal degeneration resulting in blindness. The disorder is caused by mutations in the CHM gene encoding REP-1 protein, an essential component of the Rab geranylgeranyltransferase (GGTase) complex. In the present study, we evaluated a multi-technique analysis algorithm to describe the mutational spectrum identified in a large cohort of cases and further correlate CHM variants with phenotypic characteristics and biochemical defects of choroideremia patients. Molecular genetic testing led to the characterization of 36 out of 45 unrelated CHM families (80%), allowing the clinical reclassification of four CHM families. Haplotype reconstruction showed independent origins for the recurrent p.Arg293* and p.Lys178Argfs*5 mutations, suggesting the presence of hotspots in CHM, as well as the identification of two different unrelated events involving exon 9 deletion. No certain genotype-phenotype correlation could be established. Furthermore, all the patients´ fibroblasts analyzed presented significantly increased levels of unprenylated Rabs proteins compared to control cells; however, this was not related to the genotype. This research demonstrates the major potential of the algorithm proposed for diagnosis. Our data enhance the importance of establish a differential diagnosis with other retinal dystrophies, supporting the idea of an underestimated prevalence of choroideremia. Moreover, they suggested that the severity of the disorder cannot be exclusively explained by the genotype.
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Current address: Universidad de Mogi das Cruzes, São Paulo, Brazil
Competing Interests: The authors have declared that no competing interests exist.
Current address: Instituto de Medicina Genomica, Valencia, Spain
Conceived and designed the experiments: RSA CR VK RRA CA. Performed the experiments: RSA MGH MALM NSB OZ AG CV LRJS MC RPC ST AAF. Analyzed the data: RSA MGH LRJS IL MJTT BGS MILM FBK. Contributed reagents/materials/analysis tools: RSA MALM NSB OZ AG CV MC RPC AAF. Wrote the paper: RSA CA.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0151943