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A. I. Den Hollander, T. L. McGee, E. L. Berson; Identification of a Homozygous Missense Change in IRBP in a Consanguineous Family With Autosomal Recessive Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1693.
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Retinitis pigmentosa (RP) is a heterogeneous group of retinal degenerations that can be transmitted as a dominant, recessive, or X-linked trait. Mutations in 21 genes have been associated with the recessive form. This study was done to identify the genetic defect in a consanguineous family with five siblings. Three siblings have RP, one is affected by history, and one is unaffected.
Two affected family members were genotyped with Affymetrix 250K single nucleotide polymorphism (SNP) microarrays. The genotyping data were analyzed for homozygous regions using dCHIP. Regions that were homozygous in both individuals were analyzed with selected SNPs in the other three family members to reduce the size of the target interval.
All four affected siblings shared a 9-Mb homozygous region on chromosome 10, while the unaffected sibling was not homozygous for alleles in this interval. The best candidate gene in this region is the gene encoding the interphotoreceptor retinol-binding protein (IRBP), which mediates the transport of all-trans retinol, 11-cis retinol, and 11-cis retinal between rods, cones, retinal pigment epithelium and Müller cells. Sequence analysis of the IRBP gene revealed a homozygous missense change (Asp1080Asn) in all affected individuals. This variant was not identified in 94 control individuals. The aspartic acid at position 1080 is completely conserved among all species (chicken, cow, dog, mouse, opossum, Xenopus, zebrafish) and among all four IRBP repeat modules in these species. Modeling based on the structure of a single module of Xenopus IRBP (Structure 10:43, 2002) suggests that Asp1080 participates in the retinoid-binding site scaffold, which may destabilize by the change to asparagine at this position (Drs D. Ghosh and F. Gonzalez-Fernandez, personal communication).
Previous studies showed that targeted knockout of the Irbp gene causes photoreceptor degeneration in mice, but no human disease has so far been linked to mutations in this gene. This is the first family in which a potential pathogenic variant has been identified in the IRBP gene. We are planning to evaluate the sibling who is affected by history to confirm his clinical diagnosis, and to screen the IRBP gene in additional patients with recessive RP.
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