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

• 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)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Alkyl and Aryl Transferases - genetics; Analysis; Biology and Life Sciences; Blindness; Choroideremia; Choroideremia - genetics; Clonal deletion; Degeneration; Diagnosis; Differential diagnosis; DNA Mutational Analysis - methods; Exons - genetics; Female; Fibroblasts; Gene therapy; Genetic aspects; Genetic Association Studies - methods; Genetic screening; Genetic testing; Genetics; Genotypes; Geranylgeranyltransferase; Haplotypes; Haplotypes - genetics; Hospitals; Humans; Male; Medicine and Health Sciences; Messenger RNA; Mutation; Mutation - genetics; Neurosciences; Patients; Pedigree; Physical Sciences; Proteins; Reclassification; Research and Analysis Methods; Retina; Retinal degeneration; Risk factors; X chromosome; France; Spain
• DOI: 10.1371/journal.pone.0151943
• EISSN: 1932-6203

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.