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Human Molecular Genetics, 2002, Vol. 11, No. 5 559-568
© 2002 Oxford University Press

Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa

Sara J. Bowne1, Lori S. Sullivan1, Susan H. Blanton2, Constance L. Cepko3, Seth Blackshaw3, David G. Birch4, Dianna Hughbanks-Wheaton4, John R. Heckenlively5 and Stephen P. Daiger1,6,+

1Human Genetics Center, School of Public Health, The University of Texas HSC, Houston, TX 77030, USA, 2Department of Pediatrics, University of Virginia, Charlottesville, VA 22908, USA, 3Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, 4Retina Foundation of the Southwest, Dallas, TX 75231, USA, 5Jules Stein Eye Institute, Los Angeles, CA 90095, USA and 6Department of Ophthalmology and Visual Science, The University of Texas HSC, Houston, TX 77030, USA

Autosomal dominant retinitis pigmentosa (adRP) is a heterogeneous set of progressive retinopathies caused by several distinct genes. One locus, the RP10 form of adRP, maps to human chromosome 7q31.1 and may account for 5–10% of adRP cases among Americans and Europeans. We identified two American families with the RP10 form of adRP by linkage mapping and used these families to reduce the linkage interval to 3.45 Mb between the flanking markers D7S686 and RP-STR8. Sequence and transcript analysis identified 54 independent genes within this region, at least 10 of which are retinal-expressed and thus candidates for the RP10 gene. A screen of retinal transcripts comparing retinas from normal mice to retinas from crx–/crx– knockout mice (with poorly differentiated photoreceptors) demonstrated a 6-fold reduction in one candidate, inosine monophosphate dehydrogenase 1 (IMPDH1; EC 1.1.1.205). Since many of the genes known to cause retinitis pigmentosa are under CRX control in photoreceptors, IMPDH1 became a high-priority candidate for mutation screening. DNA sequencing of affected individuals from the two American RP10 families revealed a GAC->AAC transition in codon 226 substituting an asparagine for an aspartic acid in both families. The identical mutation was also found in a British RP10 family. The Asp226Asn missense mutation is present in all affected individuals tested and absent from unaffected controls. The aspartic acid at codon 226 is conserved in all IMPDH genes, in all species examined, including bacteria, suggesting that this mutation is highly deleterious. Subsequent screening of probands from 60 other adRP families revealed an additional family with this mutation, confirming its association with retinitis pigmentosa and the relatively high frequency of this mutation. Another IMPDH1 substitution, Val268Ile, was also observed in this cohort of patients but not in controls. IMPDH1 is a ubiquitously expressed enzyme, functioning as a homotetramer, which catalyzed the rate-limiting step in de novo synthesis of guanine nucleotides. As such, it plays an important role in cyclic nucleoside metabolism within photoreceptors. Several classes of drugs are known to affect IMPDH isoezymes, including nucleotide and NAD analogs, suggesting that small-molecule therapy may be available, one day, for RP10 patients.

+ To whom correspondence should be addressed at: University of Texas-Houston Health Science Center, Human Genetics Center, PO Box 20186, Houston, TX 77225, USA. Tel: +1 713 500 9829; Fax: +1 713 500 0900; Email: sdaiger@sph.uth.tmc.edu


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