title: RP1 protein truncating mutations predominate at the RP1 adRP locus.
abstract: OBJECTIVE
  Recent reports have shown that the autosomal dominant retinitis pigmentosa (adRP) phenotype linked to the pericentric region of chromosome 8 is associated with mutations in a gene designated RP1. Screening of the whole gene in a large cohort of patients has not been undertaken to date. To assess the involvement and character of RP1 mutations in adRP, the gene was screened in a panel of 266 unrelated patients of British origin and a Pakistani family linked to this locus.
  
  
  METHODS
  Patients exhibiting the adRP phenotype were screened for mutations in the four exons of the RP1 gene by heteroduplex analysis and direct sequencing. Linkage of the Pakistani family was achieved using microsatellite markers. Polymerase chain reaction (PCR) products were separated by nondenaturing polyacrylamide gel electrophoresis. Alleles were assigned to individuals, which allowed calculation of LOD scores. Microsatellite marker haplotyping was used to determine ancestry of patients carrying the same mutation.
  
  
  RESULTS
  In the 266 British patients and 1 Pakistani family analyzed, 21 loss-of-function mutations and 7 amino acid substitutions were identified, some of which may also be disease-causing. The mutations, many of which were deletion or insertion events, were clustered in the 5' end of exon 4. Most mutations resulted in a premature termination codon in the mRNA. Haplotype analysis of nine patients carrying an R677X mutation suggested that these patients are not ancestrally related.
  
  
  CONCLUSIONS
  RP1 mutations account for 8% to 10% of the mutations in our cohort of British patients. The most common disease-causing mechanism is deduced to be one involving the presence of a truncated protein. Mutations in RP1 have now been described in adRP patients of four ethnically diverse populations. The different disease haplotype seen in the nine patients carrying the same mutation suggests that this mutation has arisen independently many times, possibly due to a mutation hot spot in this part of the gene.
authors.affiliation: Department of Molecular Genetics, Institute of Ophthalmology, Moorfields Eye Hospital, London, United Kingdom. a.payne@ucl.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Payne
authors.forename: E
authors.initials: E
authors.lastname: Vithana
authors.forename: S
authors.initials: S
authors.lastname: Khaliq
authors.forename: A
authors.initials: A
authors.lastname: Hameed
authors.forename: J
authors.initials: J
authors.lastname: Deller
authors.forename: L
authors.initials: L
authors.lastname: Abu-Safieh
authors.forename: S
authors.initials: S
authors.lastname: Kermani
authors.forename: B P
authors.initials: BP
authors.lastname: Leroy
authors.forename: S Q
authors.initials: SQ
authors.lastname: Mehdi
authors.forename: A T
authors.initials: AT
authors.lastname: Moore
authors.forename: A C
authors.initials: AC
authors.lastname: Bird
authors.forename: S S
authors.initials: SS
authors.lastname: Bhattacharya
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005136:Eye Proteins / Q000235:genetics*; D008040:Genetic Linkage; D006239:Haplotypes; D020180:Heteroduplex Analysis; D006801:Humans; D008126:Lod Score; D008869:Microtubule-Associated Proteins; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012174:Retinitis Pigmentosa / Q000235:genetics*
chemical_list: D017931:DNA Primers; D005136:Eye Proteins; D008869:Microtubule-Associated Proteins; C120042:RP1 protein, human