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PLoS One. 2016 Apr 12;11(4):e0151943. doi: 10.1371/journal.pone.0151943. eCollection 2016.

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

Author information

1
Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.
2
Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
3
Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France.
4
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
5
Department of Ophthalmology, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain.

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.

PMID:
27070432
PMCID:
PMC4829155
DOI:
10.1371/journal.pone.0151943
[Indexed for MEDLINE]
Free PMC Article

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