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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Adaptor Proteins, Signal Transducing
  • CHM protein, human
  • Alkyl and Aryl Transferases
  • Rab geranylgeranyltransferase

Grants and funding

The research leading to these results has received funding from the following research grants: Fondo de Investigación Sanitaria -FIS (PI:13/00226), the Centre for Biomedical Network Research on Rare Diseases -CIBERER (06/07/0036), the Biobank of University Hospital Fundacion Jimenez Diaz Hospital (PT13/0010/0012), ONCE, Swiss National Science Foundation (Grant Number 31003A_156260), the European Union Seventh Framework Programme [FP7-People-2012-ITN] under grant agreement 317472 (EyeTN), the patient associations France Choroideremia, Retina France and the Association Française contre les Myopathies. RSA is supported by Sara Borrell CD12/00676, MC by Miguel Servet CP13/03256 and RPC by Fundación Conchita Rábago (FCR).