Alternative titles; symbols
HGNC Approved Gene Symbol: UGP2
Cytogenetic location: 2p15 Genomic coordinates (GRCh38): 2:63,840,969-63,891,560 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p15 | Developmental and epileptic encephalopathy 83 | 618744 | Autosomal recessive | 3 |
UDP-glucose pyrophosphorylase (UGP; EC 2.7.7.9) catalyzes the transfer of a glucose moiety from glucose-1-phosphate to MgUTP, forming UDP-glucose and MgPPi (summary by Cheng et al., 1997).
Peng and Chang (1993) isolated a UGP cDNA, which they designated UDPG, by screening a human liver cDNA library for complementation of an E. coli galU mutation. The UDPG gene encodes a predicted 508-amino acid protein with no homology to the bacterial protein, but with 47% identity with potato UDPG. On Northern blots, the 2.2-kb UDPG mRNA is expressed in all tissues tested, with the highest levels in skeletal muscle.
Yu and Zheng (2012) stated that human UGPase has an N-terminal regulatory domain, a central catalytic domain, and a C-terminal domain that mediates homooligomer formation. The catalytic domain includes a highly conserved Rossmann fold characteristic of nucleotidyltransferases and nucleotide-binding proteins.
Perenthaler et al. (2020) noted that the UGP2 gene encodes 2 main isoforms, a longer isoform 1 and a shorter isoform 2, that differ by 11 amino acids at the N terminus, but are expected to be functionally equivalent. RT-PCR, Western blot analysis, and immunohistochemical studies showed that the short isoform is expressed in a broad variety of cell types during human brain development. Specific regions of expression included neuropil in the proliferative neuroepithelium of the hypothalamic, cortical, mesencephalic and thalamic regions, the marginal zone of the spinal cord, cuboidal epithelial cells of the choroid plexus, neurons in the cerebral cortex, and neurons and glial cells in the cerebellum.
Shows et al. (1978) assigned UGPP2 to chromosome 2 by means of man-mouse somatic cell hybrids. The linear order appears to be (ACP1)-(UGPP2)-(MDH-S)-(IDH-S). Cheng et al. (1997) mapped the UGP2 gene to 2p14-p13 by fluorescence in situ hybridization.
Gal- yeast are deficient in galactose-1-phosphate uridyltransferase (GALT; 606999) and cannot grow in medium containing galactose as the only carbohydrate source. Lai and Elsas (2000) found that expression of yeast Ugp1 was upregulated in surviving Gal- revertant cells. Furthermore, overexpression of yeast Ugp1 or the human ortholog, UGP2, rescued growth in Gal- yeast. Lai and Elsas (2000) concluded that UGP2 has dual function and can convert galactose-1-phosphate and UTP to form UDP-galactose, replenishing its cellular content.
Yu and Zheng (2012) determined the crystal structure of human UGPase at 3.6-angstrom resolution. Human UGPase formed octamers via a highly conserved C-terminal beta helix. End-to-end interactions between monomers resulted in formation of dimeric protomers, and 4 protomers formed a 4-leaf-clover-shaped octamer with a calculated molecular mass of 439 kD. A latch structure within the C-terminal domain of vertebrate UGPases sterically limited enzymatic activity, whereas UGPases of yeast and other lower organisms lacked the latch structure and had higher activity. Mutations within the latch motif or mutations that depolymerized human UGPase octamers elevated pyrophosphorylase activity.
Fuhring et al. (2013) found that octamerization was necessary, but not sufficient, for recombinant human UGP enzymatic activity. All mutations that disturbed octamer formation negatively impacted UGP enzymatic activity. UGP did not dissociate from the octameric state during the enzymatic cycle.
In 20 patients from 13 unrelated families with developmental and epileptic encephalopathy-83 (DEE83; 618744), Perenthaler et al. (2020) identified the same homozygous c.34A-G transition at a highly conserved nucleotide in the UGP2 gene. The mutation was predicted to result in a met12-to-val (M12V) substitution in the longer isoform (isoform 1) and to disrupt a translational start site (c.1A-G) in the shorter isoform (isoform 2), resulting in a met1-to-? substitution. Isoform 2 is highly expressed in brain and neural stem cells. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. It was not present in several large control databases, including the Exome Variant Server and Iranone databases, but was found at a low frequency (5.3 x 10(-5)) in only heterozygous state in the gnomAD database (15 of 280,902 alleles). Western blot analysis of fibroblasts from 1 patient showed absent expression of the UGP2 short isoform, with upregulation of the long isoform harboring the M12V substitution. Whereas the 2 isoforms were equally expressed in wildtype fibroblasts, the expression of the shorter isoform was diminished to 25% of total UGP2 in heterozygous patients. These findings indicated that the long isoform carrying the M12V variant is upregulated when the short isoform is missing. The M12V long isoform showed normal cellular localization and enzymatic activity in patient cells, which may explain the survival of the patients. In vitro functional cellular expression studies showed that expression of the mutation in the short UGP2 isoform and complete knockdown of the short UGP2 isoform in human embryonic stem cells resulted in disrupted programmed differentiation into neural cells. Transcriptome analysis of the mutant cells showed a signature suggesting a tendency to differentiate prematurely, as well as changes in the expression of several specific genes implicated in pathways involved in neurodevelopmental disorders. The metabolic profile of mutant cells was also abnormal, showing reduced ability to produce UDP-glucose and synthesize glycogen, impaired protein glycosylation, and increased activation of the unfolded protein response. These defects could be restored by expression of wildtype UGP2. Perenthaler et al. (2020) concluded that disruption of the brain-specific UGP2 isoform resulted in the neurologic phenotype with viability of the patients. The authors further suggested that total loss of function or complete absence of UGP2 in all cells would be embryonic lethal. The findings highlighted the emerging role of tissue-specific isoforms as a disease mechanism in genetic disorders.
Perenthaler et al. (2020) found that knockdown of zebrafish UGP2 orthologs resulted in decreased ability to produce UDP-glucose, reduced global neural activity, abnormal movements, decreased spontaneous visual movements, and possibly an increased susceptibility to seizures.
Burgerhout et al. (1973) and Van Someren et al. (1974) had mapped the structural locus for this enzyme to chromosome 1 by somatic cell studies.
In 20 patients from 13 unrelated families with infantile epileptic encephalopathy-83 (DEE83; 618744), Perenthaler et al. (2020) identified the same homozygous c.34A-G transition (NM_006759) at a highly conserved nucleotide in the UGP2 gene. The mutation was predicted to result in a met12-to-val (M12V) substitution in the longer isoform (isoform 1) and to disrupt a translational start site (c.1A-G, NM_001001521.1) in the shorter isoform (isoform 2), resulting in a met1-to-? (M1?) substitution. Isoform 2 of UGP2 is highly expressed in the brain and in neural stem cells. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. It was not present in several large control databases, including the Exome Variant Server and Iranone databases, but was found at a low frequency (5.3 x 10(-5)) in only heterozygous state in the gnomAD database (15 of 280,902 alleles). Western blot analysis of fibroblasts from 1 patient showed absent expression of the UGP2 short isoform, with upregulation of the long isoform harboring the M12V substitution. Whereas the 2 isoforms were equally expressed in wildtype fibroblasts, the expression of the shorter isoform was diminished to 25% of total UGP2 in heterozygous patients. These findings indicated that the long isoform carrying the M12V variant is upregulated when the short isoform is missing. The M12V long isoform showed normal cellular localization and enzymatic activity in patient cells, which may explain the survival of the patients. The families were of Middle Eastern descent, including Pakistani, Iranian, Saudi Arabian, Indian, and Omani, and haplotype analysis of several individuals suggested a founder effect. Although 1 family (family 1) was Dutch, the authors noted that Dutch traders settled in the region around Balochistan in the 17th century. The mutation was estimated to have originated about 26 generations or 600 years ago. Two additional patients from 2 additional unrelated families with a similar phenotype were also reported, although clinical details were not provided. Onset of the disorder in the patients ranged from the first days of life to about 7 months of age.
Burgerhout, W., Van Someren, H., Bootsma, D. Cytological mapping of the gene assigned to the human A1 chromosome by the use of radiation induced chromosome breakage in a human-Chinese hamster hybrid cell line. Humangenetik 20: 159-162, 1973. [PubMed: 4785162] [Full Text: https://doi.org/10.1007/BF00284852]
Cheng, S.-D., Peng, H.-L., Chang, H.-Y. Localization of the human UGP2 gene encoding the muscle isoform of UDPglucose pyrophosphorylase to 2p13-p14 by fluorescence in situ hybridization. Genomics 39: 414-416, 1997. [PubMed: 9119383] [Full Text: https://doi.org/10.1006/geno.1996.4426]
Fuhring, J., Damerow, S., Fedorov, R., Schneider, J., Munster-Kuhnel, A.-K., Gerardy-Schahn, R. Octamerization is essential for enzymatic function of human UDP-glucose pyrophosphorylase. Glycobiology 23: 426-437, 2013. [PubMed: 23254995] [Full Text: https://doi.org/10.1093/glycob/cws217]
Lai, K., Elsas, L. J. Overexpression of human UDP-glucose pyrophosphorylase rescues galactose-1-phosphate uridyltransferase-deficient yeast. Biochem. Biophys. Res. Commun. 271: 392-400, 2000. [PubMed: 10799308] [Full Text: https://doi.org/10.1006/bbrc.2000.2629]
Peng, H.-L., Chang, H.-Y. Cloning of a human liver UDP-glucose pyrophosphorylase cDNA by complementation of the bacterial galU mutation. FEBS Lett. 329: 153-158, 1993. [PubMed: 8354390] [Full Text: https://doi.org/10.1016/0014-5793(93)80213-e]
Perenthaler, E., Nikoncuk, A., Yousefi, S., Berdowski, W. M., Alsagob, M., Capo, I., van der Linde, H. C., van den Berg, P., Jacobs, E. H., Putar, D., Ghazvini, M., Aronica, E., and 57 others. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases. Acta Neuropath. 139: 415-442, 2020. [PubMed: 31820119] [Full Text: https://doi.org/10.1007/s00401-019-02109-6]
Shows, T. B., Brown, J. A., Goggin, A. P., Haley, L. L., Byers, M. G., Eddy, R. L. Assignment of a molecular form of UDP glucose pyrophosphorylase (UGPP-2) to chromosome 2 in man. Cytogenet. Cell Genet. 22: 215-218, 1978. [PubMed: 752477] [Full Text: https://doi.org/10.1159/000130939]
Van Someren, H., Van Henegouwen, H. B., Westerveld, A., Bootsma, D. Synteny of the human loci for fumarate hydratase and UDPG pyrophosphorylase with chromosome 1 markers in somatic cell hybrids. Cytogenet. Cell Genet. 13: 551-557, 1974. [PubMed: 4549862] [Full Text: https://doi.org/10.1159/000130306]
Yu, Q., Zheng, X. The crystal structure of human UDP-glucose pyrophosphorylase reveals a latch effect that influences enzymatic activity. Biochem. J. 442: 283-291, 2012. [PubMed: 22132858] [Full Text: https://doi.org/10.1042/BJ20111598]