title: Identification of an IMPDH1 mutation in autosomal dominant retinitis pigmentosa (RP10) revealed following comparative microarray analysis of transcripts derived from retinas of wild-type and Rho(-/-) mice.
abstract: Comparative analysis of the transcriptional profiles of approximately 6000 genes in the retinas of wild-type mice with those carrying a targeted disruption of the rhodopsin gene was undertaken by microarray analysis. This revealed a series of transcripts, of which some were derived from genes known to map at retinopathy loci, levels of which were reduced or elevated in the retinas of Rho(-/-) mice lacking functional photoreceptors. The human homologue of one of these genes, encoding inosine monophosphate dehydrogenase type 1 (IMPDH1), maps to the region of 7q to which an adRP gene (RP10) had previously been localized. Mutational screening of DNA from the Spanish adRP family, originally used to localize the RP10 gene, revealed an Arg224Pro substitution co-segregating with the disease phenotype. The amino acid at position 224 of the IMPDH1 protein is conserved among species and the substitution is not present in healthy, unrelated individuals of European origin. These data provide strong evidence that mutations within the IMPDH1 gene cause adRP, and validate approaches to mutation detection involving comparative analysis of global transcription profiles in normal and degenerating retinal tissues. Other genes showing significant alterations in expression include some with anti-apoptotic functions and many encoding components of the extracellular matrix or cytoskeleton, a possible reflection of a response by Muller cells to preserve the remaining outer nuclear layer of the retina. We suggest that those genes identified are prime candidates for etiological involvement in degenerative retinal disease.
authors.affiliation: The Ocular Genetics Unit, Department of Genetics, Trinity College, Dublin 2, Ireland.
authors.forename: Avril
authors.initials: A
authors.lastname: Kennan
authors.forename: Aileen
authors.initials: A
authors.lastname: Aherne
authors.forename: Arpad
authors.initials: A
authors.lastname: Palfi
authors.forename: Marian
authors.initials: M
authors.lastname: Humphries
authors.forename: Alex
authors.initials: A
authors.lastname: McKee
authors.forename: Alan
authors.initials: A
authors.lastname: Stitt
authors.forename: David A C
authors.initials: DA
authors.lastname: Simpson
authors.forename: Karin
authors.initials: K
authors.lastname: Demtroder
authors.forename: Torben
authors.initials: T
authors.lastname: Orntoft
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kenna
authors.forename: G Jane
authors.initials: GJ
authors.lastname: Farrar
authors.forename: Pete
authors.initials: P
authors.lastname: Humphries
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002897:Chromosomes, Human, Pair 7; D017124:Conserved Sequence; D020869:Gene Expression Profiling; D005799:Genes, Dominant; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012160:Retina / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics*; D012243:Rhodopsin / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D012243:Rhodopsin; D001120:Arginine; D007168:IMP Dehydrogenase; C463299:IMPDH1, mouse