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

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Serval ID
serval:BIB_5597FAAEA693
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice.
Journal
Plos One
Author(s)
Sanchez-Alcudia R., Garcia-Hoyos M., Lopez-Martinez M.A., Sanchez-Bolivar N., Zurita O., Gimenez A., Villaverde C., Rodrigues-Jacy da Silva L., Corton M., Perez-Carro R., Torriano S., Kalatzis V., Rivolta C., Avila-Fernandez A., Lorda I., Trujillo-Tiebas M.J., Garcia-Sandoval B., Lopez-Molina M.I., Blanco-Kelly F., Riveiro-Alvarez R., Ayuso C.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
11
Number
4
Pages
e0151943
Language
english
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.
Keywords
Adaptor Proteins, Signal Transducing/genetics, Alkyl and Aryl Transferases/genetics, Choroideremia/genetics, DNA Mutational Analysis/methods, Exons/genetics, Female, Genetic Association Studies/methods, Haplotypes/genetics, Humans, Male, Mutation/genetics, Pedigree
Pubmed
Web of science
Open Access
Yes
Create date
19/04/2016 17:12
Last modification date
20/08/2019 14:10
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