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Annette Payne, Eranga Vithana, Shagufta Khaliq, Abdul Hameed, Jane Deller, Leen Abu-Safieh, Sana Kermani, Bart P. Leroy, S. Qasim Mehdi, Anthony T. Moore, Alan C. Bird, Shomi S. Bhattacharya; RP1 Protein Truncating Mutations Predominate at the RP1 adRP Locus. Invest. Ophthalmol. Vis. Sci. 2000;41(13):4069-4073.
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purpose. 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
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
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