title: A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice.
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.
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Sanchez-Alcudia
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Hoyos
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Lopez-Martinez
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Sanchez-Bolivar
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Zurita
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Ascension
authors.initials: A
authors.lastname: Gimenez
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Villaverde
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.
authors.forename: Luciana
authors.initials: L
authors.lastname: Rodrigues-Jacy da Silva
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Perez-Carro
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France.
authors.forename: Simona
authors.initials: S
authors.lastname: Torriano
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Kalatzis
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Avila-Fernandez
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lorda
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Trujillo-Tiebas
authors.affiliation: Department of Ophthalmology, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Garcia-Sandoval
authors.affiliation: Department of Ophthalmology, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Lopez-Molina
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blanco-Kelly
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Riveiro-Alvarez
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D019883:Alkyl and Aryl Transferases / Q000235:genetics; D015794:Choroideremia / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase