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HGNC Approved Gene Symbol: IMPDH1
Cytogenetic location: 7q32.1 Genomic coordinates (GRCh38) : 7:128,392,277-128,409,982 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q32.1 | Leber congenital amaurosis 11 | 613837 | Autosomal dominant | 3 |
| Retinitis pigmentosa 10 | 180105 | Autosomal dominant | 3 |
Inosine-5-prime-monophosphate dehydrogenase (EC 1.1.1.205) catalyzes the formation of xanthine monophosphate (XMP) from IMP. In the purine de novo synthetic pathway, IMP dehydrogenase is positioned at the branch point in the synthesis of adenine and guanine nucleotides and is thus the rate-limiting enzyme in the de novo synthesis of guanine nucleotides. Inhibition of cellular IMP dehydrogenase activity results in an abrupt cessation of DNA synthesis and a cell cycle block at the G1-S interface (summary by Collart and Huberman, 1988).
Collart and Huberman (1988) used a polyclonal antibody directed against the purified protein to isolate human and Chinese hamster IMP dehydrogenase cDNA clones. The sequence of these clones demonstrated an open reading frame for a protein containing 514 amino acids. The molecular mass of the produced protein was 56 kD, which is the observed molecular mass of the purified protein and of the immunoprecipitated in vitro translation product. A high order of conservation of the IMP dehydrogenase protein was indicated by the finding that human and Chinese hamster cDNA clones differed by only 8 amino acids.
Natsumeda et al. (1990) isolated 2 distinct cDNAs (types I and II) encoding IMP dehydrogenase from a human spleen cDNA library. Both clones encode proteins of 514 residues showing 84% sequence identity. Type I mRNA was found to be the main species in normal leukocytes, and type II (146691) predominated in human ovarian tumors.
By polymerase chain reaction analysis of a panel of human/mouse and human/hamster cell somatic hybrids using primers specific for the IMPDH1 gene and by fluorescence in situ hybridization with metaphase chromosomes using IMPDH1 genomic DNA as probes, Gu et al. (1994) established that the IMPDH1 gene is located on 7q31.3-q32.
Pseudogene
Doggett et al. (1993) described a randomly generated STS from human chromosome 16 genomic DNA that had 90% sequence identity to IMPDH1 and 72% identity to IMPDH2. By PCR analysis of a panel of somatic cell hybrids containing different portions of human chromosome 16, they mapped the IMPDH-like sequence to 16p13.3-p13.12. This regional mapping assignment was further refined to subband 16p13.13 by high-resolution FISH. The presence of an intron and frameshift mutations in IMPDHL1 suggested that the locus may be an unprocessed pseudogene.
Autosomal dominant retinitis pigmentosa (adRP) is a heterogeneous set of progressive retinopathies caused by several distinct genes. One locus, RP10 (180105), maps to human chromosome 7q31.1 and may account for 5 to 10% of adRP cases among Americans and Europeans. By linkage mapping, Bowne et al. (2002) identified 2 American families with the RP10 form of adRP and used these families to reduce the linkage interval to 3.45 Mb between the flanking markers D7S686 and RP-STR8. Ten retinal transcripts were identified among 54 independent genes within the candidate region, including IMPDH1. DNA sequencing of affected individuals from 3 RP10 families revealed an asp226-to-asn substitution (D226N; 146690.0001). Asp226 is highly evolutionarily conserved among IMPDH genes, suggesting that this mutation may be highly deleterious. Another IMPDH1 substitution, val268 to ile (V268I; 146690.0002), was observed in one of a cohort of 60 adRP families but not in controls. IMPDH1 is a ubiquitously expressed enzyme, functioning as a homotetramer, which catalyzes the rate-limiting step in de novo synthesis of guanine nucleotides. As such, it may play an important role in cyclic nucleotide metabolism within photoreceptors.
Kennan et al. (2002) used microarray analysis to compare retinal transcript levels between wildtype mice and those with a targeted disruption of the rhodopsin gene (180380), designated Rho -/-. The IMPDH1 gene was identified among a series of transcripts present at reduced levels. Mutation screening of DNA from a Spanish adRP family revealed an arg224-to-pro substitution (R224P; 146690.0003) cosegregating with the disease phenotype. Arg224 of the IMPDH1 protein is conserved among species, and the substitution was not present in a European control cohort, providing additional evidence that the mutation is responsible for the disease phenotype.
Bowne et al. (2006) searched for mutations in the IMPDH1 gene in 265 patients with retinitis pigmentosa, 17 patients with macular degeneration, and 24 patients with Leber congenital amaurosis (see LCA11, 613837). They identified 5 variants in 8 families with autosomal dominant RP. They also identified heterozygous variants in 2 patients with isolated LCA11 (R105W, 146690.0004; N198K, 146690.0005). None of the identified variants altered the enzymatic activity of the corresponding proteins; in all apparently pathogenic mutations, the affinity and/or the specificity of single-stranded nucleic acid binding was altered.
Aherne et al. (2004) determined that the bulk of GTP within photoreceptors of mice was generated by IMPDH1. Impdh1 -/- null mice displayed a slowly progressive form of retinal degeneration in which visual transduction, analyzed by electroretinographic wave functions, became gradually compromised, although at 12 months of age most photoreceptors remained structurally intact. Aherne et al. (2004) noted that, in contrast, the human form of RP caused by mutations in the IMPDH1 gene is a severe autosomal dominant degenerative retinopathy. Expression of mutant IMPDH1 proteins in bacterial and mammalian cells, together with computational simulations, indicated that protein misfolding and aggregation, rather than reduced IMPDH1 enzyme activity, was the likely cause of the severe phenotype in the human form.
In a murine model of autosomal dominant RP (RP10; 180105) involving expression of an arg224-to-pro mutation within the IMPDH1 gene, Tam et al. (2010) showed that treatment with 17-allylamino-17-demethoxygeldanamycin (17-AAG), an ansamycin antibiotic that binds to heat-shock protein Hsp90 (HSP90AA1; 140571), activated a heat-shock response in mammalian cells. The treatment protected photoreceptors against degeneration induced by aggregating mutant IMPDH1 protein. Systemic delivery of the drug to the retina was facilitated by claudin-5 (CLDN5; 602101) siRNA-mediated modulation of the inner-blood retina barrier. The authors proposed that a single low molecular weight drug has the potential to suppress aggregation of a wide range of mutant proteins causing RP.
Among 3 families with autosomal dominant retinitis pigmentosa linked to 7q (RP10; 180105), Bowne et al. (2002) identified a G-to-A transition at codon 226 of the IMPDH1 gene, substituting an asparagine for an aspartic acid (D226N). Asp226 is highly evolutionarily conserved among IMPDH genes, suggesting that this mutation may be highly deleterious.
Wada et al. (2005) identified the D226N mutation in 6 of 183 unrelated patients with autosomal dominant RP. Taking into account the 135 patients excluded from the study because of previously identified mutations in other dominant RP genes, Wada et al. (2005) estimated that IMPDH1 mutations account for approximately 2% of cases of dominant RP in North America. Based on a comparison of electroretinogram (ERG) amplitudes among carriers of the IMPDH1 D226N mutation, the RP1 mutation R677X (603937.0001), the rhodopsin mutation P23H (180380.0001), and the rhodopsin mutation P347L (180380.0002), Wada et al. (2005) concluded that D226N, the most frequent mutation, appeared to cause at least as much loss of rod function as cone function, and that patients with this form of RP retained, on average, 2 to 5 times more ERG amplitude per unit of remaining visual area than patients with the 3 other forms of dominant RP.
Bischof et al. (2006) identified a processed pseudogene for IMPDH1 carrying the 676G-A transition that produces the D226N substitution. The authors suggested that this case may represent a novel gene conversion event involving a processed pseudogene.
In a family with autosomal dominant retinitis pigmentosa linked to 7q (RP10; 180105), Bowne et al. (2002) identified a G-to-A transition at codon 268 of the IMPDH1 gene, substituting an isoleucine for valine (V268I). The mutation was absent among a European control cohort.
In a Spanish family with autosomal dominant retinitis pigmentosa linked to 7q (RP10; 180105), Kennan et al. (2002) identified a G-to-C transition in codon 224 of the IMPDH1 gene, substituting proline for arginine. Arg224 is highly evolutionarily conserved among IMPDH genes, suggesting that this mutation may be highly deleterious.
In a patient (family UTAD463) with isolated Leber congenital amaurosis-11 (613837), Bowne et al. (2006) identified heterozygosity for a 313C-T transition in the IMPDH1 gene, resulting in an arg105-to-trp (R105W) substitution. The mutation is located at the junction of the CBS subdomain and alters the nucleic acid binding properties of IMPDH1.
In a patient (family UTAD391) with isolated Leber congenital amaurosis-11 (LCA11; 613837), Bowne et al. (2006) identified heterozygosity for a 594T-G transversion in the IMPDH1 gene, resulting in an asn198-to-lys (N198K) substitution. The mutation is located at the junction of the CBS subdomain and alters the nucleic acid binding properties of IMPDH1. The mutation was not found in the unaffected parents or in an unaffected sister.
In a French Canadian man with retinitis pigmentosa-10 (RP10; 180105), Coussa et al. (2015) identified heterozygosity for a c.954G-C transversion in the IMPDH1 gene, resulting in a gln318-to-his (Q318H) substitution. Functional studies of the variant were not performed.
Aherne, A., Kennan, A., Kenna, P. F., McNally, N., Lloyd, D. G., Alberts, I. L., Kiang, A.-S,, Humphries, M. M., Ayuso, C., Engel, P. C., Gu, J. J., Mitchell, B. S., Farrar, G. J., Humphries, P. On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa. Hum. Molec. Genet. 13: 641-650, 2004. [PubMed: 14981049] [Full Text: https://doi.org/10.1093/hmg/ddh061]
Bischof, J. M., Chiang, A. P., Scheetz, T. E., Stone, E. M., Casavant, T. L., Sheffield, V. C., Braun, T. A. Genome-wide identification of pseudogenes capable of disease-causing gene conversion. Hum. Mutat. 27: 545-552, 2006. [PubMed: 16671097] [Full Text: https://doi.org/10.1002/humu.20335]
Bowne, S. J., Sullivan, L. S., Blanton, S. H., Cepko, C. L., Blackshaw, S., Birch, D. G., Hughbanks-Wheaton, D., Heckenlively, J. R., Daiger, S. P. Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa. Hum. Molec. Genet. 11: 559-568, 2002. [PubMed: 11875050] [Full Text: https://doi.org/10.1093/hmg/11.5.559]
Bowne, S. J., Sullivan, L. S., Mortimer, S. E., Hedstrom, L., Zhu, J., Spellicy, C. J., Gire, A. I., Hughbanks-Wheaton, D., Birch, D. G., Lewis, R. A., Heckenlively, J. R., Daiger, S. P. Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and Leber congenital amaurosis. Invest. Ophthal. Vis. Sci. 47: 34-42, 2006. [PubMed: 16384941] [Full Text: https://doi.org/10.1167/iovs.05-0868]
Collart, F. R., Huberman, E. Cloning and sequence analysis of the human and Chinese hamster inosine-5-prime-monophosphate dehydrogenase cDNAs. J. Biol. Chem. 263: 15769-15772, 1988. [PubMed: 2902093]
Coussa, R. G., Chakarova, C., Ajlan, R., Taha, M., Kavalec, C., Gomolin, J., Khan, A., Lopez, I., Ren, H., Waseem, N., Kamenarova, K., Bhattacharya, S. S., Koenekoop, R. K. Genotype and phenotype studies in autosomal dominant retinitis pigmentosa (adRP) of the French Canadian founder population. Invest. Ophthal. Vis. Sci. 56: 8297-8305, 2015. Note: Erratum: Invest. Ophthal. Vis. Sci. 58: 4768 only, 2017. [PubMed: 26720483] [Full Text: https://doi.org/10.1167/iovs.15-17104]
Doggett, N. A., Callen, D. F., Chen, Z. L., Moore, S., Tesmer, J. G., Duesing, L. A., Stallings, R. L. Identification and regional localization of a human IMP dehydrogenase-like locus (IMPDHL1) at 16p13.13. Genomics 18: 687-689, 1993. [PubMed: 7905856] [Full Text: https://doi.org/10.1016/s0888-7543(05)80374-x]
Gu, J. J., Kaiser-Rogers, K., Rao, K., Mitchell, B. S. Assignment of the human type I IMP dehydrogenase gene (IMPDH1) to chromosome 7q31.3-q32. Genomics 24: 179-181, 1994. [PubMed: 7896275] [Full Text: https://doi.org/10.1006/geno.1994.1597]
Kennan, A., Aherne, A., Palfi, A., Humphries, M., McKee, A., Stitt, A., Simpson, D. A. C., Demtroder, K., Orntoft, T., Ayuso, C., Kenna, P. F., Farrar, G. J., Humphries, P. 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. Hum. Molec. Genet. 11: 547-558, 2002. [PubMed: 11875049] [Full Text: https://doi.org/10.1093/hmg/11.5.547]
Natsumeda, Y., Ohno, S., Kawasaki, H., Konno, Y., Weber, G., Suzuki, K. Two distinct cDNAs for human IMP dehydrogenase. J. Biol. Chem. 265: 5292-5295, 1990. [PubMed: 1969416]
Tam, L. C. S., Kiang, A.-S., Campbell, M., Keaney, J., Farrar, G. J., Humphries, M. M., Kenna, P. F., Humphries, P. Prevention of autosomal dominant retinitis pigmentosa by systemic drug therapy targeting heat shock protein 90 (Hsp90). Hum. Molec. Genet. 19: 4421-4436, 2010. [PubMed: 20817636] [Full Text: https://doi.org/10.1093/hmg/ddq369]
Wada, Y., Sandberg, M. A., McGee, T. L., Stillberger, M. A., Berson, E. L., Dryja, T. P. Screen of the IMPDH1 gene among patients with dominant retinitis pigmentosa and clinical features associated with the most common mutation, Asp226Asn. Invest. Ophthal. Vis. Sci. 46: 1735-1741, 2005. [PubMed: 15851576] [Full Text: https://doi.org/10.1167/iovs.04-1197]