title: Analysis of the PRPF31 Gene in Spanish Autosomal Dominant Retinitis Pigmentosa Patients: A Novel Genomic Rearrangement.
abstract: The aim was to determine the prevalence of PRPF31 mutations in a cohort of Spanish autosomal dominant retinitis pigmentosa (adRP) families to deepen knowledge of the pathogenic mechanisms underlying the disease and to assess genotype-phenotype correlations.
  
  
  
  A cohort of 211 adRP patients was screened for variants in PRPF31 by using a combined strategy comprising next-generation sequencing approaches and copy-number variation (CNV) analysis. Quantitative RT-PCR and CNV analysis of the regulatory MSR1 element were also performed to assess PRPF31 gene expression. Phenotype was assessed by using ophthalmologic examination protocols.
  
  
  
  Fifteen different causative mutations and genomic rearrangements were identified, revealing five novel mutations. Prevalence of PRPF31 mutations, genomic rearrangements, and lack of penetrance were 7.6%, 1.9%, and 66.7%, respectively. Interestingly, we identified a tandem duplication and a partial PRPF31 deletion in different affected individuals from the same family. PRPF31 gene expression was significantly decreased in symptomatic cases carrying either PRPF31 duplication or deletion as compared to controls. The 4 MSR1 allele in cis with the PRPF31 wild-type allele was apparently a protective factor. The mutated phenotype varied from no symptoms to typical retinitis pigmentosa with variable onset and course depending on the kind of mutation, with the duplication case the most severe.
  
  
  
  In view of the high genetic heterogeneity of PRPF31 mutations, the screening must include the entire gene, as well as CNV assays, to detect large rearrangements. This is the first report of a variable phenotype correlation as well as a gross duplication and deletion within the same family.
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Martin-Merida
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (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 University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernandez-San Jose
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (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 University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Perez-Carro
authors.affiliation: Universidade de Mogi das Cruzes, São Paulo, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Rodriguez-Jacy da Silva
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
authors.forename: Berta
authors.initials: B
authors.lastname: Almoguera
authors.affiliation: Department of Ophthalmology, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Garcia-Sandoval
authors.affiliation: Department of Ophthalmology, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), 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 University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Avila-Fernandez
authors.affiliation: Molecular Genetics Unit, Hospital de Terrassa, Terrassa, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carballo
authors.affiliation: Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (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 University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain 2Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
mesh_terms: D000328:Adult; D000483:Alleles; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015995:Prevalence; D012326:RNA Splicing / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D013030:Spain / Q000453:epidemiology
chemical_list: D005136:Eye Proteins; C454222:PRPF31 protein, human