A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement

Sara J. Bowne, Marian M. Humphries, Lori S. Sullivan, Paul F. Kenna, Lawrence C.S. Tam, Anna S. Kiang, Matthew Campbell, George M. Weinstock, Daniel C. Koboldt, Li Ding, Robert S. Fulton, Erica J. Sodergren, Denis Allman, Sophia Millington-Ward, Arpad Palfi, Alex McKee, Susan H. Blanton, Susan Slifer, Ioanna Konidari, G. Jane FarrarStephen P. Daiger, Peter Humphries

Research output: Contribution to journalArticlepeer-review

117 Scopus citations


Linkage testing using Affymetrix 6.0 SNP Arrays mapped the disease locus in TCD-G, an Irish family with autosomal dominant retinitis pigmentosa (adRP), to an 8.8 Mb region on 1p31. Of 50 known genes in the region, 11 candidates, including RPE65 and PDE4B, were sequenced using di-deoxy capillary electrophoresis. Simultaneously, a subset of family members was analyzed using Agilent SureSelect All Exome capture, followed by sequencing on an Illumina GAIIx platform. Candidate gene and exome sequencing resulted in the identification of an Asp477Gly mutation in exon 13 of the RPE65 gene tracking with the disease in TCD-G. All coding exons of genes not sequenced to sufficient depth by next generation sequencing were sequenced by di-deoxy sequencing. No other potential disease-causing variants were found to segregate with disease in TCD-G. The Asp477Gly mutation was not present in Irish controls, but was found in a second Irish family provisionally diagnosed with choroideremia, bringing the combined maximum two-point LOD score to 5.3. Mutations in RPE65 are a known cause of recessive Leber congenital amaurosis (LCA) and recessive RP, but no dominant mutations have been reported. Protein modeling suggests that the Asp477Gly mutation may destabilize protein folding, and mutant RPE65 protein migrates marginally faster on SDS-PAGE, compared with wild type. Gene therapy for LCA patients with RPE65 mutations has shown great promise, raising the possibility of related therapies for dominant-acting mutations in this gene.

Original languageEnglish
Pages (from-to)1074-1081
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number10
StatePublished - Oct 2011


  • RPE65
  • choroideremia
  • exome capture
  • next-generation sequencing
  • retinitis pigmentosa


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