title: Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population.
abstract: OBJECTIVE
  We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype.
  
  
  METHODS
  Case series.
  
  
  METHODS
  A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls.
  
  
  METHODS
  High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography.
  
  
  METHODS
  Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings.
  
  
  RESULTS
  Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions.
  
  
  CONCLUSIONS
  This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population.
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Avila-Fernandez
authors.affiliation: Instituto de Genética Médica y Molecular, IdiPaz, Hospital Universitario La Paz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Vallespín
authors.affiliation: Department of Ophthalmology, Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: López-Molina
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Almoguera
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Martín-Garrido
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Sorina D
authors.initials: SD
authors.lastname: Tatu
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: M Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blanco-Kelly
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Riveiro-Alvarez
authors.affiliation: Genetics of Cardiovascular and Ophthalmologic Diseases, Instituto de Investigación Sanitaria de Santiago de Compostela, RIC, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Brión
authors.affiliation: Department of Ophthalmology, Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: García-Sandoval
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FPM
authors.lastname: Cremers
authors.affiliation: Genomic Medicine Group-USC, Fundación Publica Galega de Medicina Xenómica, Santiago de Compostela, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases, ISCIII, Valencia, Spain. Electronic address: cayuso@fjd.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
mesh_terms: D000328:Adult; D002648:Child; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics*; D046228:Microarray Analysis; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013030:Spain; D014792:Visual Acuity; D014794:Visual Fields; D055815:Young Adult
chemical_list: D005136:Eye Proteins; C522405:LCA5 protein, human; D008869:Microtubule-Associated Proteins