title: Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa.
abstract: OBJECTIVE
  Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes.
  
  
  METHODS
  We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing.
  
  
  RESULTS
  We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family.
  
  
  CONCLUSIONS
  The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin.
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors: Paola
authors: P
authors: Benaglio
authors: Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors: Patricia Fernandez
authors: PF
authors: San Jose
authors: Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors: Almudena
authors: A
authors: Avila-Fernandez
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors: Giulia
authors: G
authors: Ascari
authors: The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA.
authors: Shyana
authors: S
authors: Harper
authors: INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital Saint Eloi, Montpellier, France.
authors: Gaël
authors: G
authors: Manes
authors: Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors: Carmen
authors: C
authors: Ayuso
authors: INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital Saint Eloi, Montpellier, France.
authors: Christian
authors: C
authors: Hamel
authors: The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA.
authors: Eliot L
authors: EL
authors: Berson
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors: Carlo
authors: C
authors: Rivolta
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods*; D005799:Genes, Dominant; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016366:Open Reading Frames / Q000235:genetics; D010445:Peptide Elongation Factors / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000235:genetics; D017415:Ribonucleoprotein, U5 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics
chemical_list: C581608:EFTUD2 protein, human; C489982:PRPF4 protein, human; D010445:Peptide Elongation Factors; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D017415:Ribonucleoprotein, U5 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear; C402291:Snu13 protein, human