Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (16)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Aherne, A.
Right arrow Articles by Humphries, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aherne, A.
Right arrow Articles by Humphries, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2004, Vol. 13, No. 6 641-650
DOI: 10.1093/hmg/ddh061

On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa

Aileen Aherne1,*, Avril Kennan1, Paul F. Kenna1,2, Niamh McNally1, David G. Lloyd3, Ian L. Alberts3, Anna-Sophia Kiang1, Marian M. Humphries1, Carmen Ayuso4, Paul C. Engel5, Jing Jin Gu6, Beverly S. Mitchell6, G. Jane Farrar1 and Pete Humphries1

1The Ocular Genetics Unit, Department of Genetics, Trinity College Dublin, Dublin 2, Ireland, 2Research Foundation, Eye and Ear Hospital, Dublin 2, Ireland, 3De Novo Pharmaceuticals, Compass House, Vision Park Histon, Cambridge CB4 9ZR, UK, 4Fundacion Jimenez Diaz, Clinica de Nuestra Senora de la Conception, Avda de los Reyes Catolicos 2 (Ciudad Universitaria), 28040 Madrid, Spain, 5Department of Biochemistry and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland and 6Lineberger Comprehensive Cancer Center, Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA

Received November 7, 2003; Accepted January 12, 2004

Retinitis pigmentosa (RP), the hereditary degenerative disease of the photoreceptor neurons of the retina, probably represents the most prevalent cause of registered blindness amongst those of working age in developed countries. Mutations within the gene encoding inosine monophosphate dehydrogenase 1 (IMPDH1), the widely expressed rate-limiting enzyme of the de novo pathway of guanine nucleotide biosynthesis, have recently been shown to cause the RP10 form of autosomal dominant RP. We examined the expression of IMPDH1, IMPDH2 and HPRT transcripts, encoding enzymes of the de novo and salvage pathways of guanine nucleotide biosynthesis, respectively, in retinal sections of mice, the data indicating that the bulk of GTP within photoreceptors is generated by IMPDH1. Impdh1–/– null mice are shown here to display a slowly progressive form of retinal degeneration in which visual transduction, analysed by electroretinographic wave functions, becomes gradually compromised, although at 12 months of age most photoreceptors remain structurally intact. In contrast, the human form of RP caused by mutations within the IMPDH1 gene is a severe autosomal dominant degenerative retinopathy in those families that have been examined to date. Expression of mutant IMPDH1 proteins in bacterial and mammalian cells, together with computational simulations, indicate that protein misfolding and aggregation, rather than reduced IMPDH1 enzyme activity, is the likely cause of the severe phenotype experienced by human subjects. Taken together, these findings suggest that RP10 may represent an attractive target for therapeutic intervention, based upon a strategy combining simultaneous suppression of transcripts from normal and mutant IMPDH1 alleles with supplementation of GTP within retinal tissues.

* To whom correspondence should be addressed. Tel: +353 16082484; Fax: +353 16083848; Email: aaherne{at}tcd.ie


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
L. C.S. Tam, A.-S. Kiang, A. Kennan, P. F. Kenna, N. Chadderton, M. Ader, A. Palfi, A. Aherne, C. Ayuso, M. Campbell, et al.
Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10)
Hum. Mol. Genet., July 15, 2008; 17(14): 2084 - 2100.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
D. Trifunovic, M. Karali, D. Camposampiero, D. Ponzin, S. Banfi, and V. Marigo
A High-Resolution RNA Expression Atlas of Retinitis Pigmentosa Genes in Human and Mouse Retinas
Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2330 - 2336.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Ji, J. Gu, A. M. Makhov, J. D. Griffith, and B. S. Mitchell
Regulation of the Interaction of Inosine Monophosphate Dehydrogenase with Mycophenolic Acid by GTP
J. Biol. Chem., January 6, 2006; 281(1): 206 - 212.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
S. J. Bowne, L. S. Sullivan, S. E. Mortimer, L. Hedstrom, J. Zhu, C. J. Spellicy, A. I. Gire, D. Hughbanks-Wheaton, D. G. Birch, R. A. Lewis, et al.
Spectrum and Frequency of Mutations in IMPDH1 Associated with Autosomal Dominant Retinitis Pigmentosa and Leber Congenital Amaurosis
Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 34 - 42.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
Y. Wada, M. A. Sandberg, T. L. McGee, M. A. Stillberger, E. L. Berson, and T. P. Dryja
Screen of the IMPDH1 Gene among Patients with Dominant Retinitis Pigmentosa and Clinical Features Associated with the Most Common Mutation, Asp226Asn
Invest. Ophthalmol. Vis. Sci., May 1, 2005; 46(5): 1735 - 1741.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.