Alternative titles; symbols
HGNC Approved Gene Symbol: NT5C2
Cytogenetic location: 10q24.32-q24.33 Genomic coordinates (GRCh38): 10:103,088,017-103,193,272 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.32-q24.33 | Spastic paraplegia 45, autosomal recessive | 613162 | Autosomal recessive | 3 |
Purine 5-prime-nucleotidase (EC 3.1.3.5) preferentially hydrolyzes inosine 5-prime-monophosphate (IMP) and other purine nucleotides, and is allosterically activated by various compounds, including ATP. The enzyme is exclusively located in the cytoplasmic matrix of cells and may have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases (summary by Oka et al., 1994).
Oka et al. (1994) found 2 distinct but closely related types of cDNAs for purine 5-prime-nucleotidase in a chicken liver cDNA library. The encoded A- and B-type proteins were similar throughout a central core of 472 amino acids sharing 79% sequence identity. Using degenerate oligonucleotides based on identical portions of amino acid sequences between A- and B-type subunits of the chicken enzyme, Oka et al. (1994) isolated human cytosolic purine 5-prime-nucleotidase cDNA clones with PCR. The predicted open reading frame encoded a protein of 561 amino acids with a molecular mass of 64,966 Da. The deduced amino acid sequence exhibited 95% identity with the sequence of the B-type subunit of chicken enzyme. Northern blot analysis of placental polyadenylated RNA revealed a single band of 3.6 kb.
Gross (2014) mapped the NT5C2 gene to chromosome 10q24.32-q24.33 based on an alignment of the NT5C2 sequence (GenBank BC001595) with the genomic sequence (GRCh37).
Spastic Paraplegia 45
In affected members of the consanguineous Turkish family with spastic paraplegia-45 (SPG45; 613162) mapped to chromosome 10q24-q25 by Dursun et al. (2009), Novarino et al. (2014) identified a homozygous nonsense mutation in the NT5C2 gene (R29X; 600417.0001). In affected members of 4 other families with SPG45 recognized from a large exome sequencing project of consanguineous families with neurologic disease, they identified homozygosity for 1 other nonsense (600417.0004), 1 frameshift (600417.0002), and 2 splice site mutations (600417.0003; 600417.0005) in the NT5C2 gene.
Acute Lymphoblastic Leukemia Relapse
Heterozygous activating mutations in NT5C2 are present in about 20% of relapsed pediatric T-cell ALL (613065) and in 3 to 10% of relapsed B-precursor ALL, and an arg367-to-gln (R367Q) change is the most common NT5C2 mutation found in relapsed ALL. Tzoneva et al. (2018) used a conditional and inducible leukemia model to demonstrate that expression of NT5C2(R367Q) induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukemia cell growth and leukemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2 +/R367Q mutant cells was associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5-prime-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukemia lymphoblasts. Tzoneva et al. (2018) concluded that these results identified the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and supported a role for IMPDH inhibition in the treatment of ALL.
Johanns et al. (2019) found that NT5C2 knockout mice had reduced body weight, adipose tissue, and insulin resistance, with improved glucose tolerance compared to wildtype mice when both were fed a high fat diet. The authors provided evidence suggesting that this effect is due to increased responsiveness of skeletal muscle to insulin.
In the 2 Turkish sibs with spastic paraplegia-45 (SPG45; 613162) reported by Dursun et al. (2009), Novarino et al. (2014) identified a homozygous c.86G-A transition in the NT5C2 gene, resulting in an arg29-to-ter (R29X) substitution.
In 2 affected sisters from a consanguineous family (family 1290) segregating spastic paraplegia-45 (SPG45; 613162), Novarino et al. (2014) identified homozygosity for a 1-bp deletion (c.1225delA) in the NT5C2 gene, resulting in a frameshift and premature termination (Ser409Valfs436Ter). None of the unaffected family members were homozygous for this mutation.
In 2 affected sisters from a consanguineous family (family 1549) segregating spastic paraplegia-45 (SPG45; 613162), Novarino et al. (2014) identified homozygosity for an acceptor splice site mutation (c.988-1G-T) in the NT5C2 gene. None of the unaffected family members were homozygous for this mutation.
In 2 affected brothers from a consanguineous family (family 1829) segregating spastic paraplegia-45 (SPG45; 613162), Novarino et al. (2014) identified homozygosity for a c.445A-T transversion in the NT5C2 gene, resulting in an arg149-to-ter (R149X) substitution. None of the unaffected family members were homozygous for this mutation.
In 2 affected sibs from a consanguineous family (family 659) segregating spastic paraplegia-45 (SPG45; 613162), Novarino et al. (2014) identified homozygosity for a donor splice site mutation (c.175+1G-A). None of the unaffected family members were homozygous for this mutation.
Dursun, U., Koroglu, C., Orhan, E.K., Ugur, S. A., Tolun, A. Autosomal recessive spastic paraplegia (SPG45) with mental retardation maps to 10q24.3-q25.1. Neurogenetics 10: 325-331, 2009. [PubMed: 19415352] [Full Text: https://doi.org/10.1007/s10048-009-0191-3]
Gross, M. B. Personal Communication. Baltimore, Md. 2/27/2014.
Johanns, M., Kviklyte, S., Chuang, S.-J., Corbeels, K., Jacobs, R., Herinckx, G., Vertommen, D, Schakman, O., Duparc, T., Cani, P. D., Bouzin, C., Andersen, H., Bohlooly-Y, M., Van der Schueren, B., Oscarsson, J., Rider, M. H. Genetic deletion of soluble 5-prime-nucleotidase II reduces body weight gain and insulin resistance induced by a high-fat diet. Molec. Genet. Metab. 126: 377-387, 2019. [PubMed: 30803894] [Full Text: https://doi.org/10.1016/j.ymgme.2019.01.017]
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014. [PubMed: 24482476] [Full Text: https://doi.org/10.1126/science.1247363]
Oka, J., Matsumoto, A., Hosokawa, Y., Inoue, S. Molecular cloning of human cytosolic purine 5-prime-nucleotidase. Biochem. Biophys. Res. Commun. 205: 917-922, 1994. [PubMed: 7999131] [Full Text: https://doi.org/10.1006/bbrc.1994.2752]
Tzoneva, G., Dieck, C. L., Oshima, K., Ambesi-Impiombato, A., Sanchez-Martin, M., Madubata, C. J., Khiabanian, H., Yu, J., Waanders, E., Iacobucci, I., Sulis, M. L., Kato, M., and 9 others. Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia. Nature 553: 511-514, 2018. [PubMed: 29342136] [Full Text: https://doi.org/10.1038/nature25186]