Identification of KLHL7 as a Novel Gene for adRP

Abstract

Purpose: : Retinitis Pigmentosa constitutes a group of heterogenous genetic eye diseases in which the photoreceptor cells in the retina degenerate, leading to irreversible vision loss. To date, 18 genes have been identified to cause autosomal dominant retinitis pigmentosa (adRP) (RetNet). We are studying a large Scandinavian family with a slower than average progression rate and apparent autosomal dominant pattern of inheritance.

Methods: : We performed linkage analysis using the data obtained by hybridiziation of affected individual DNAs to 250K gene chip SNP arrays from Affymetrix. SNP data was examined using standard methods (Pedstats, GRR etc), and linkage was performed using Merlin. We identified a peak lod score of 5.0 on chromosome 7p15. No mutations were identified in a previously-reported RP9 gene, Pim-1 kinase associated protein, at 7p14. We performed a screen of genes in the minimal region as determined through haplotype analysis.

Results: : A G>A heterozygous alteration was observed in exon 6 of KLHL7. This mutation is predicted to generate a serine to asparagine amino acid change in the Back domain of KLHL7. The mutation segregated with the disease and was not present in unaffected individuals or spouses within the family. We did not observe this change in Scandinavian or in North American control individuals. A C>T heterozygous change in exon 6 was observed in two separate families, one from the U.K. and a second from Scandinavia. Further work is being performed to validate this mutation and to screen for additional mutations in KLHL7. Immunoblot analysis demonstrated KLHL7 expression in the retina, consistent with the hypothesis that mutations in KLHL7 lead to retinopathy.

Conclusions: : The identification of KLHL7 as an adRP gene will assist in the better understanding of the molecular mechanisms underlying RP and could lead to targeted therapies to alleviate this disease.

Keywords: gene screening • retinal degenerations: hereditary • mutations