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Human Molecular Genetics, 2002, Vol. 11, No. 5 547-558
© 2002 Oxford University Press

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

Avril Kennan1,+, Aileen Aherne1, Arpad Palfi1,2, Marian Humphries1, Alex McKee1, Alan Stitt3, David A. C. Simpson3, Karin Demtroder4, Torben Orntoft4, Carmen Ayuso5, Paul F. Kenna1, G. Jane Farrar1 and Pete Humphries1

1The Ocular Genetics Unit, Department of Genetics, Trinity College, Dublin 2, Ireland, 2University of Szeged, Szeged, Hungary, 3Department of Ophthalmology, The Queen’s University of Belfast, Belfast, UK, 4Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Brendstrupgaardsvej, DK-8200 Aarhus N/Skejby, Denmark and 5Fundacion Jimenez Diaz, Clinica de Nuestra Senora de la Concepcion, Avda de los Reyes Catolicos 2 (Ciudad Universitaria), 28040 Madrid, Spain

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.

+ To whom correspondence should be addressed. Tel: +353 1 6082484; Fax: +353 1 6083848; Email: akennan@tcd.ie


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