A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice.pdf (1.13 MB)
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A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice.

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posted on 03.11.2017, 11:29 by Rocio Sanchez-Alcudia, Maria Garcia-Hoyos, Miguel A. Lopez-Martinez, Noelia Sanchez-Bolivar, Olga Zurita, Ascension Gimenez, Cristina Villaverde, Luciana Rodrigues-Jacy da Silva, Marta Corton, Raquel Perez-Carro, Simona Torriano, Vasiliki Kalatzis, Carlo Rivolta, Almudena Avila-Fernandez, Isabel Lorda, Maria J. Trujillo-Tiebas, Blanca Garcia-Sandoval, Maria I. Lopez-Molina, Fiona Blanco-Kelly, Rosa Riveiro-Alvarez, Carmen Ayuso
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.

History

Citation

PLoS One, 2016, 11 (4): e0151943

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics

Version

VoR (Version of Record)

Published in

PLoS One

Publisher

Public Library of Science

eissn

1932-6203

Acceptance date

07/03/2016

Copyright date

2016

Available date

03/11/2017

Publisher version

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151943

Language

en