* 146690

IMP DEHYDROGENASE 1; IMPDH1


Alternative titles; symbols

INOSINE-5-PRIME-MONOPHOSPHATE DEHYDROGENASE, TYPE I; IMPD1
IMPD


Other entities represented in this entry:

IMP DEHYDROGENASE-LIKE 1, INCLUDED; IMPDHL1, INCLUDED

HGNC Approved Gene Symbol: IMPDH1

Cytogenetic location: 7q32.1     Genomic coordinates (GRCh38): 7:128,392,277-128,409,982 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q32.1 Leber congenital amaurosis 11 613837 AD 3
Retinitis pigmentosa 10 180105 AD 3

TEXT

Description

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).


Cloning and Expression

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.


Mapping

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.


Molecular Genetics

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.


Animal Model

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.


ALLELIC VARIANTS ( 6 Selected Examples):

.0001 RETINITIS PIGMENTOSA 10

IMPDH1, ASP226ASN
  
RCV000015959...

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.


.0002 RETINITIS PIGMENTOSA 10

IMPDH1, VAL268ILE
  
RCV000015960...

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.


.0003 RETINITIS PIGMENTOSA 10

IMPDH1, ARG224PRO
  
RCV000015961...

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.


.0004 LEBER CONGENITAL AMAUROSIS 11

IMPDH1, ARG105TRP
  
RCV000015962...

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.


.0005 LEBER CONGENITAL AMAUROSIS 11

IMPDH1, ASN198LYS
  
RCV000015963

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.


.0006 RETINITIS PIGMENTOSA 10

IMPDH1, GLN318HIS
  
RCV000240659

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.


REFERENCES

  1. 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, related citations] [Full Text]

  2. 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, related citations] [Full Text]

  3. 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, images, related citations] [Full Text]

  4. 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, images, related citations] [Full Text]

  5. 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, related citations]

  6. 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, related citations] [Full Text]

  7. 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, related citations] [Full Text]

  8. 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, related citations] [Full Text]

  9. 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, related citations] [Full Text]

  10. 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, related citations]

  11. 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, related citations] [Full Text]

  12. 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, related citations] [Full Text]


George E. Tiller - updated : 09/13/2017
Jane Kelly - updated : 09/07/2016
George E. Tiller - updated : 11/29/2006
Jane Kelly - updated : 9/11/2006
Victor A. McKusick - updated : 7/12/2006
Jane Kelly - updated : 11/16/2005
George E. Tiller - updated : 10/4/2002
George E. Tiller - updated : 10/3/2002
Creation Date:
Victor A. McKusick : 11/30/1988
carol : 09/20/2018
carol : 05/31/2018
alopez : 09/13/2017
carol : 09/07/2016
joanna : 08/04/2016
carol : 03/25/2011
joanna : 7/27/2010
alopez : 3/19/2010
carol : 4/3/2009
carol : 11/29/2006
carol : 9/11/2006
alopez : 7/19/2006
terry : 7/12/2006
alopez : 11/16/2005
cwells : 10/4/2002
cwells : 10/3/2002
terry : 11/15/2001
carol : 9/22/1999
terry : 12/5/1994
supermim : 3/16/1992
carol : 6/8/1990
supermim : 3/20/1990
ddp : 10/27/1989
root : 11/30/1988

* 146690

IMP DEHYDROGENASE 1; IMPDH1


Alternative titles; symbols

INOSINE-5-PRIME-MONOPHOSPHATE DEHYDROGENASE, TYPE I; IMPD1
IMPD


Other entities represented in this entry:

IMP DEHYDROGENASE-LIKE 1, INCLUDED; IMPDHL1, INCLUDED

HGNC Approved Gene Symbol: IMPDH1

Cytogenetic location: 7q32.1     Genomic coordinates (GRCh38): 7:128,392,277-128,409,982 (from NCBI)


Gene-Phenotype Relationships

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

TEXT

Description

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).


Cloning and Expression

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.


Mapping

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.


Molecular Genetics

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.


Animal Model

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.


ALLELIC VARIANTS 6 Selected Examples):

.0001   RETINITIS PIGMENTOSA 10

IMPDH1, ASP226ASN
SNP: rs121912550, gnomAD: rs121912550, ClinVar: RCV000015959, RCV000255540, RCV003887871

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.


.0002   RETINITIS PIGMENTOSA 10

IMPDH1, VAL268ILE
SNP: rs121912551, gnomAD: rs121912551, ClinVar: RCV000015960, RCV002513068

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.


.0003   RETINITIS PIGMENTOSA 10

IMPDH1, ARG224PRO
SNP: rs121912552, ClinVar: RCV000015961, RCV003887872

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.


.0004   LEBER CONGENITAL AMAUROSIS 11

IMPDH1, ARG105TRP
SNP: rs121912553, gnomAD: rs121912553, ClinVar: RCV000015962, RCV000951177, RCV003887873

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.


.0005   LEBER CONGENITAL AMAUROSIS 11

IMPDH1, ASN198LYS
SNP: rs121912554, gnomAD: rs121912554, ClinVar: RCV000015963

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.


.0006   RETINITIS PIGMENTOSA 10

IMPDH1, GLN318HIS
SNP: rs886037911, ClinVar: RCV000240659

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.


REFERENCES

  1. 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]

  2. 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]

  3. 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]

  4. 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]

  5. 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]

  6. 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]

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Contributors:
George E. Tiller - updated : 09/13/2017
Jane Kelly - updated : 09/07/2016
George E. Tiller - updated : 11/29/2006
Jane Kelly - updated : 9/11/2006
Victor A. McKusick - updated : 7/12/2006
Jane Kelly - updated : 11/16/2005
George E. Tiller - updated : 10/4/2002
George E. Tiller - updated : 10/3/2002

Creation Date:
Victor A. McKusick : 11/30/1988

Edit History:
carol : 09/20/2018
carol : 05/31/2018
alopez : 09/13/2017
carol : 09/07/2016
joanna : 08/04/2016
carol : 03/25/2011
joanna : 7/27/2010
alopez : 3/19/2010
carol : 4/3/2009
carol : 11/29/2006
carol : 9/11/2006
alopez : 7/19/2006
terry : 7/12/2006
alopez : 11/16/2005
cwells : 10/4/2002
cwells : 10/3/2002
terry : 11/15/2001
carol : 9/22/1999
terry : 12/5/1994
supermim : 3/16/1992
carol : 6/8/1990
supermim : 3/20/1990
ddp : 10/27/1989
root : 11/30/1988