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

Sanchez-Alcudia, Rocio and Garcia-Hoyos, Maria and Lopez-Martinez, Miguel Angel and Sanchez-Bolivar, Noelia and Zurita, Olga and Gimenez, Ascension and Villaverde, Cristina and Rodrigues-Jacy da Silva, Luciana and Corton, Marta and Perez-Carro, Raquel and Torriano, Simona and Kalatzis, Vasiliki and Rivolta, Carlo and Avila-Fernandez, Almudena and Lorda, Isabel and Trujillo-Tiebas, Maria J. and Garcia-Sandoval, Blanca and Lopez-Molina, Maria Isabel and Blanco-Kelly, Fiona and Riveiro-Alvarez, Rosa and Ayuso, Carmen. (2016) A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice. PLoS ONE, 11 (4). e0151943.

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Abstract

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.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Public Library of Science
e-ISSN:1932-6203
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:03 Mar 2021 09:52
Deposited On:03 Mar 2021 09:52

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