Other entities represented in this entry:
HGNC Approved Gene Symbol: ODC1
SNOMEDCT: 1222658006;
Cytogenetic location: 2p25.1 Genomic coordinates (GRCh38) : 2:10,439,968-10,448,327 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p25.1 | Bachmann-Bupp syndrome | 619075 | Autosomal dominant | 3 |
Ornithine decarboxylase (EC 4.1.1.17) catalyzes the conversion of ornithine to putrescine in the first and apparently rate-limiting step in polyamine biosynthesis. The activity of the enzyme fluctuates rapidly in response to various growth-promoting stimuli, and ODC exhibits one of the most rapid turnover rates of mammalian proteins. Winqvist et al. (1986) used a mouse cDNA probe to isolate human cDNA clones from a library prepared from human liver mRNA. Unlike the mouse genome, there are only a few ODC genes in the human genome.
Hickok et al. (1987) deduced the complete amino acid sequence of human ODC from a complementary cDNA.
Ornithine decarboxylase, the first enzyme in polyamine synthesis, is a transcriptional target of MYC (190080) and a modifier of APC (611731)-dependent tumorigenesis. ODC promoter activity is influenced by cooperative interactions involving neighboring E-boxes (Walhout et al., 1997). A polymorphic site, situated between 2 E-boxes, was identified in the human ODC promoter and shown to affect MYC-dependent ODC promoter activity in rodent fibroblasts (Guo et al., 2000). A GC box in the proximal promoter of the ODC1 gene is required for basal and induced transcriptional activity. Law et al. (1998) determined that SP1 (189906) and ZBP89 (601897) bound to this region in a mutually exclusive manner, and that ZBP89 inhibited SP1-activated ODC1 promoter activity following transfection in insect cells.
Translation of ODC, the rate-limiting enzyme in the biosynthesis of polyamines, peaks twice during the cell cycle, at the G1/S transition and at G2/M. Pyronnet et al. (2000) identified a cap-independent internal ribosome entry site (IRES) in the ODC mRNA that functions exclusively at G2/M. This ensures elevated levels of polyamines, which are implicated in mitotic spindle formation and chromatin condensation. MYC mRNA also contains an IRES that functions during mitosis. Thus, Pyronnet et al. (2000) concluded that IRES-dependent translation is likely to be a general mechanism to synthesize short-lived proteins even at mitosis, when cap-dependent translation is interdicted.
Winqvist et al. (1986) observed that human DNA fragments segregated with 2pter-p23 and 7cen-qter in mouse-human somatic cell hybrids containing rearranged chromosomes. Despite the fact that that segment of chromosome 2 contains the NMYC gene (164840), which is involved in a number of neoplasms, coamplification of ODC was not found. The ODC gene on chromosome 2 was tentatively called ODC1 and that on 7 ODC2 (ODCP).
Yang-Feng et al. (1987) assigned ODC to 2p25-p24 by Southern blot analysis of DNA from somatic cell hybrids and by in situ hybridization. They also assigned the corresponding gene in the mouse to chromosome 12. ODC is presumably closely linked to RRM2 (180390) because both are amplified in human and mouse hydroxyurea-resistant cells. By in situ hybridization, Radford et al. (1987) narrowed the localization to 2p25. The chromosome 2 locus appears to be the functional ODC gene.
Cox et al. (1988) used a genomic probe specific for a functional mouse Odc gene in conjunction with a panel of Chinese hamster x mouse somatic cell hybrids to assign Odc to mouse chromosome 12. There is considerable genetic homology between a region of mouse chromosome 12 and the distal short arm of human chromosome 2. Villani et al. (1989) also presented data on the mapping of Odc on mouse chromosome 12.
Pseudogenes
Using a chromosomal rearrangement and somatic cell hybrids, Radford et al. (1987) assigned the ODC2 locus to 7q31-qter. This pseudogene is also symbolized ODCP.
In 4 unrelated patients with Bachmann-Bupp syndrome (BABS; 619075), Rodan et al. (2018) identified de novo heterozygous mutations in the ODC1 gene (165640.0002-165640.0005). All of the mutations were identified by trio whole-exome sequencing. The resultant proteins were predicted to escape nonsense-mediated decay and to have a truncated C terminus, leading to decreased protein degradation and a net increase in enzyme activity. Rodan et al. (2018) noted that the close proximity of the mutations suggested a mutation hotspot. A gain in ODC activity was supported by increased N-acetylputrescine levels in plasma from one of the patients.
Bupp et al. (2018) identified a de novo heterozygous nonsense mutation in the ODC1 gene (K448X; 165640.0006) in a 32-month-old girl with BABS. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Molecular modeling suggested that due to lack of a C terminus in the mutant protein, antizyme binding does not induce ODC degradation, leading to accumulation of active protein.
Associations Pending Confirmation
Martinez et al. (2003) assessed the relationship between an ODC polymorphism (165640.0001) and the risk of abnormal recurrence in participants in a colon cancer prevention trial. They further investigated whether this association was modified by aspirin use. Epidemiologic analyses revealed a substantial and statistically significant affect of the ODC polymorphism on risk of adenoma recurrence and aspirin uses. They presented experimental studies in cell culture models that may explain the epidemiologic results, suggesting that one likely mechanism for both ODC polymorphism and aspirin is their effect on intracellular polyamine pools.
This variant, formerly titled COLONIC ADENOMA RECURRENCE, REDUCED RISK OF, has been reclassified as a polymorphism.
A G-A single-nucleotide polymorphism (SNP) is positioned between 2 E boxes in intron 1 at +316 of the ODC1 gene.
Colonic Adenoma Recurrence, Reduced Risk of
Martinez et al. (2003) found that individuals homozygous for the minor ODC1 A allele who reported using aspirin were 0.10 times as likely to have an adenoma recurrence as non-aspirin users homozygous for the major G allele. MAD1 selectively suppressed the activity of the ODC1 promoter containing the A allele, but not the G allele, in a human colon cancer-derived cell line. Aspirin did not affect ODC1 allele-specific promoter activity but did activate polyamine catabolism and lower polyamine content in the same colon cancer-derived cell line. Martinez et al. (2003) suggested that the ODC1 polymorphism and aspirin act independently to reduce the risk of adenoma recurrence by suppressing synthesis and activating catabolism, respectively, of colonic mucosal polyamines. These findings confirm the hypothesis that the ODC1 polymorphism is a genetic marker for colon cancer risk, and support the use of ODC1 inhibitors and aspirin, or other nonsteroidal antiinflammatory drugs (NSAIDs), in combination as a strategy for colon cancer prevention.
Hamosh (2020) noted that this variant is present in 10,196 of 31,084 alleles and in 1,685 homozygotes in the gnomAD database (10/13/2020).
In a 7-year-old boy (patient 1) with Bachmann-Bupp syndrome (BABS; 619075), Rodan et al. (2018) identified a de novo heterozygous splice site mutation (c.1241+1G-T, NM_001287190.1) in intron 11 of the ODC1 gene. The mutation, which was identified by trio whole-exome sequencing, was predicted to destroy a canonical splice site. The resultant protein was predicted to escape nonsense-mediated decay and to have a truncated C terminus, leading to decreased protein degradation and a net increase in enzyme activity. The mutation was not present in the gnomAD database. Elevated N-acetylputrescine was demonstrated in patient plasma.
In a 16-year-old girl (patient 2) with Bachmann-Bupp syndrome (BABS; 619075), Rodan et al. (2018) identified a de novo heterozygous 2-bp duplication (c.1240_1241dupTG, NM_001287190.1) in the ODC1 gene, resulting in a frameshift and an early termination codon (Trp414CysfsTer17). The mutation was identified by trio whole-exome sequencing. The resultant protein was predicted to escape nonsense-mediated decay and to have a truncated C terminus, leading to decreased protein degradation and a net increase in enzyme activity.
In an 8-year-old boy (patient 3) with Bachmann-Bupp syndrome (BABS; 619075), Rodan et al. (2018) identified a de novo heterozygous c.1255C-T transition (c.1255C-T, NM_001287190.1), resulting in a gln419-to-ter (Q419X) substitution. The mutation was identified by trio whole-exome sequencing. The resultant protein was predicted to escape nonsense-mediated decay and to have a truncated C terminus, leading to decreased protein degradation and a net increase in enzyme activity.
In a male infant who was stillborn at 34 weeks' gestation with Bachmann-Bupp syndrome (BABS; 619075), Rodan et al. (2018) identified a de novo heterozygous 22-bp deletion (c.1242_1263del22, NM_001287190.1) in the ODC1 gene, resulting in a trp414-to-ter (W414X) substitution. The mutation was identified by trio whole-exome sequencing. The resultant protein was predicted to escape nonsense-mediated decay and to have a truncated C terminus, leading to decreased protein degradation and a net increase in enzyme activity.
In a 32-month-old girl with Bachmann-Bupp syndrome (BABS; 619075), Bupp et al. (2018) identified a de novo heterozygous c.1342A-T transversion (c.1342A-T, NM_001287190.1) in the ODC1 gene, resulting in a lys448-to-ter (K448X) substitution. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Neither parent had the mutation. Molecular modeling suggested that due to lack of a C terminus in the mutant protein, antizyme binding does not induce degradation, which leads to accumulation of active ODC protein. Western blotting showed an elevation of ODC protein levels in patient red blood cells. Elevated putrescine was demonstrated in patient red blood cells.
Alhonen-Hongisto, L., Leinonen, P., Sinervirta, R., Laine, R., Winqvist, R., Alitalo, K., Janne, O. A., Janne, J. Mouse and human ornithine decarboxylase genes: methylation polymorphism and amplification. Biochem. J. 242: 205-210, 1987. [PubMed: 3036086] [Full Text: https://doi.org/10.1042/bj2420205]
Brabant, M., McConlogue, L., van Daalen Wetters, T., Coffino, P. Mouse ornithine decarboxylase gene: cloning, structure, and expression. Proc. Nat. Acad. Sci. 85: 2200-2204, 1988. [PubMed: 3353375] [Full Text: https://doi.org/10.1073/pnas.85.7.2200]
Bupp, C. P., Schultz, C. R., Uhl, K. L., Rajasekaran, S., Bachmann, A. S. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. Am. J. Med. Genet. 176A: 2548-2553, 2018. [PubMed: 30239107] [Full Text: https://doi.org/10.1002/ajmg.a.40523]
Cox, D. R., Trouillot, T., Ashley, P. L., Brabant, M., Coffino, P. A functional mouse ornithine decarboxylase gene (Odc) maps to chromosome 12: further evidence of homoeology between mouse chromosome 12 and the short arm of human chromosome 2. Cytogenet. Cell Genet. 48: 92-94, 1988. [PubMed: 3197454] [Full Text: https://doi.org/10.1159/000132597]
Guo, Y., Harris, R. B., Rosson, D., Boorman, D., O'Brien, T. G. Functional analysis of human ornithine decarboxylase alleles. Cancer Res. 60: 6314-6317, 2000. [PubMed: 11103791]
Hamosh, A. Personal Communication. Baltimore, Md. 10/13/2020.
Hickok, N. J., Seppanen, P. J., Gunsalus, G. L., Janne, O. A. Complete amino acid sequence of human ornithine decarboxylase deduced from complementary DNA. DNA 6: 179-187, 1987. [PubMed: 3595418] [Full Text: https://doi.org/10.1089/dna.1987.6.179]
Law, G. L., Itoh, H., Law, D. J., Mize, G. J., Merchant, J. L., Morris, D. R. Transcription factor ZBP-89 regulates the activity of the ornithine decarboxylase promoter. J. Biol. Chem. 273: 19955-19964, 1998. [PubMed: 9685330] [Full Text: https://doi.org/10.1074/jbc.273.32.19955]
Martinez, M. E., O'Brien, T. G., Fultz, K. E., Babbar, N., Yerushalmi, H., Qu, N., Guo, Y., Boorman, D., Einspahr, J., Alberts, D. S., Gerner, E. W. Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. Proc. Nat. Acad. Sci. 100: 7859-7864, 2003. [PubMed: 12810952] [Full Text: https://doi.org/10.1073/pnas.1332465100]
Pyronnet, S., Pradayrol, L., Sonenberg, N. A cell cycle-dependent internal ribosome entry site. Molec. Cell 5: 607-616, 2000. [PubMed: 10882097] [Full Text: https://doi.org/10.1016/s1097-2765(00)80240-3]
Radford, D. M., Nakai, H., Byers, M. G., Eddy, R. L., Haley, L. L., Henry, W. M., Shows, T. B. Mapping the ornithine decarboxylase gene (ODC1 and ODC2) to 2p25 and 7q31-qter, respectively. (Abstract) Cytogenet. Cell Genet. 46: 678 only, 1987.
Rodan, L. H., Anyane-Yeboa, K., Chong, K., Wassink-Ruiter, J. S., Wilson, A., Smith, L., Kothare, S. V., Rajabi, F., Blaser, S., Ni, M., DeBerardinis, R. J., Poduri, A., Berry, G. T. Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities. Am. J. Med. Genet. 176A: 2554-2560, 2018. [PubMed: 30475435] [Full Text: https://doi.org/10.1002/ajmg.a.60677]
Villani, V., Coffino, P., D'Eustachio, P. Linkage genetics of mouse ornithine decarboxylase (Odc). Genomics 5: 636-638, 1989. [PubMed: 2575591] [Full Text: https://doi.org/10.1016/0888-7543(89)90035-9]
Walhout, A. J. M., Gubbels, J. M., Bernards, R., van der Vliet, P. C., Timmers, H. T. M. c-Myc/Max heterodimers bind cooperatively to the E-box sequences located in the first intron of the rat ornithine decarboxylase (ODC) gene. Nucleic Acids Res. 25: 1493-1501, 1997. [PubMed: 9162900] [Full Text: https://doi.org/10.1093/nar/25.8.1493]
Winqvist, R., Makela, T. P., Seppanen, P., Janne, O. A., Alhonen-Hongisto, L., Janne, J., Grzeschik, K.-H., Alitalo, K. Human ornithine decarboxylase sequences map to chromosome regions 2pter-p23 and 7cen-qter but are not coamplified with the NMYC oncogene. Cytogenet. Cell Genet. 42: 133-140, 1986. [PubMed: 3755388] [Full Text: https://doi.org/10.1159/000132266]
Yang-Feng, T. L., Barton, D. E., Thelander, L., Lewis, W. H., Srinivasan, P. R., Francke, U. Ribonucleotide reductase M2 subunit sequences mapped to four different chromosomal sites in humans and mice: functional locus identified by its amplification in hydroxyurea-resistant cell lines. Genomics 1: 77-86, 1987. [PubMed: 3311968] [Full Text: https://doi.org/10.1016/0888-7543(87)90108-x]