Alternative titles; symbols
HGNC Approved Gene Symbol: NT5E
SNOMEDCT: 718602007;
Cytogenetic location: 6q14.3 Genomic coordinates (GRCh38): 6:85,450,083-85,495,784 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q14.3 | Calcification of joints and arteries | 211800 | Autosomal recessive | 3 |
Ecto-5-prime-nucleotidase (5-prime-ribonucleotide phosphohydrolase; EC 3.1.3.5) catalyzes the conversion at neutral pH of purine 5-prime mononucleotides to nucleosides, the preferred substrate being AMP. The enzyme consists of a dimer of 2 identical 70-kD subunits bound by a glycosyl phosphatidyl inositol linkage to the external face of the plasma membrane. The enzyme is used as a marker of lymphocyte differentiation. Consequently, a deficiency of NT5 occurs in a variety of immunodeficiency diseases (e.g., see 102700, 300755). Other forms of 5-prime nucleotidase exist in the cytoplasm and lysosomes and can be distinguished from ecto-NT5 by their substrate affinities, requirement for divalent magnesium ion, activation by ATP, and inhibition by inorganic phosphate.
Misumi et al. (1990) cloned and sequenced a cDNA for placental 5-prime-nucleotidase.
In human-Chinese hamster hybrids, Boyle et al. (1988) found a 100% correlation between NT5 enzyme activity and presence of human chromosome 6. The correlation was confirmed by study of hybrid cells containing chromosome 6 which were stained by indirect immunofluorescence for HLA class 1 antigen and sorted by a fluorescence-activated cell sorter. Cells that were HLA negative were also NT5 negative; cells that were HLA positive were NT5 positive. Boyle et al. (1989) regionalized the NT5 gene to 6q14-q21 by study of a panel of human-mouse hybrids that contained fragments of chromosome 6 as translocations.
Adrian et al. (2000) analyzed the expression of several purinergic receptors, as well as CD73 and CD39 (ENTPD1; 601752), during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. CD73 expression was hardly detectable in undifferentiated cells and following granulocyte differentiation. Monocytic differentiation resulted in a marked upregulation of CD73 mRNA. Low expression was detected in normal blood leukocytes.
Fausther et al. (2017) identified Elf2 (619798) as a transcription factor that negatively regulated expression of Nt5e in activated mouse liver myofibroblasts during hepatic fibrosis.
Badimon et al. (2020) identified microglia as critical modulators of neuronal activity and associated behavioral responses in mice. Microglia responded to neuronal activation by suppressing neuronal activity, and ablation of microglia amplified and synchronized neuronal activity, leading to seizures. Suppression of neuronal activation by microglia occurred in a highly region-specific fashion and depended on the ability of microglia to sense and catabolize extracellular ATP released upon neuronal activation by neurons and astrocytes. ATP triggered recruitment of microglial protrusions and was converted by the microglial ATP/ADP hydrolyzing ectoenzyme Cd39 into AMP. AMP was then converted into adenosine by Cd73, which is expressed on microglia and other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and adenosine-mediated suppression of neuronal responses via the adenosine A1 receptor were essential for regulation of neuronal activity and animal behavior.
In 5 affected sibs from a consanguineous family of English descent with calcifications of arteries and joints mapping to chromosome 6q14 (CALJA; 211800), St. Hilaire et al. (2011) analyzed 3 candidate genes and identified homozygosity for a nonsense mutation in the NT5E gene (S221X; 129190.0001). Analysis of NT5E in 3 affected Italian sisters revealed homozygosity for a missense mutation (C358Y; 129190.0002), and the proband from a third family was found to be a compound heterozygote for S221X and a frameshift mutation (129190.0003). St. Hilaire et al. (2011) noted that CD73 participates in the extracellular pathway that converts ATP to adenosine on the surface of various types of cells. ENPP1 (173335) produces AMP and pyrophosphate from ATP; then CD73 produces adenosine and inorganic phosphate from AMP. Mutation in the ENPP1 gene causes generalized arterial calcification of infancy (208000).
Adenosine mediates the renal tubuloglomerular feedback-induced vascular response elicited by changes in the NaCl concentration (Sun et al., 2001; see adenosine A1 receptor, 102775). To determine whether adenosine formation depends on extracellular nucleotide hydrolysis, Castrop et al. (2004) generated mice with a targeted deletion of ecto-5-prime-nucleotidase. There was no difference in blood pressure, blood and urine chemistry, and renal blood flow between null and wildtype mice; however, whereas tubuloglomerular feedback responses did not change significantly during prolonged loop of Henle perfusion in wildtype mice, a complete disappearance of the residual feedback response was noted in null mice over 10 minutes of perfusion. Castrop et al. (2004) concluded that the generation of adenosine at the glomerular pole depends to a major extent on ecto-5-prime-nucleotidase-mediated dephosphorylation of 5-prime-AMP.
In 5 affected sibs from a consanguineous family of English descent with calcification of arteries and joints (CALJA; 211800), St. Hilaire et al. (2011) identified homozygosity for a 662C-A transversion in exon 3 of the NT5E gene, resulting in a ser221-to-ter (S221X) substitution. The unaffected third-cousin parents were heterozygous for the mutation, which was not found in 400 alleles from ethnically matched controls. Cultured fibroblasts from affected family members showed markedly reduced expression of NT5E mRNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals; rescue using a CD73-encoding lentiviral vector resulted in normalized CD73 and alkaline phosphatase activity. In another proband with calcification of arteries and joints, St. Hilaire et al. (2011) identified compound heterozygosity for the S221X mutation and a frameshift mutation in the NT5E gene (129190.0003).
In 3 Italian sisters, born of distantly related parents, who had calcification of arteries and joints (CALJA; 211800), St. Hilaire et al. (2011) identified homozygosity for a 1073G-A transition in exon 5 of the NT5E gene, resulting in a cys358-to-tyr (C358Y) substitution at a conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in 400 alleles from ethnically matched controls. Transfection studies in HEK293 cells showed negligible CD73 activity with the mutant compared to controls.
In a 44-year-old woman with extensive calcification of distal arteries and joints (CALJA; 211800), St. Hilaire et al. (2011) identified compound heterozygosity for the S221X mutation (129190.0001) and a 1-bp duplication (1609dupA) of the NT5E gene, predicted to result in a premature termination codon (Val537fsTer7). Neither mutation was present in 400 alleles from ethnically matched controls. Transfection studies in HEK293 cells showed negligible CD73 activity with the mutant compared to controls.
Adrian, K., Bernhard, M. K., Breitinger, H.-G., Ogilvie, A. Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochim. Biophys. Acta 1492: 127-138, 2000. [PubMed: 11004484] [Full Text: https://doi.org/10.1016/s0167-4781(00)00094-4]
Badimon, A., Strasburger, H. J., Ayata, P., Chen, X., Nair, A., Ikegami, A., Hwang, P., Chan, A. T., Graves, S. M., Uweru, J. O., Ledderose, C., Kutlu, M. G., and 18 others. Negative feedback control of neuronal activity by microglia. Nature 586: 417-423, 2020. [PubMed: 32999463] [Full Text: https://doi.org/10.1038/s41586-020-2777-8]
Boyle, J. M., Hey, Y., Fox, M. Human ecto-5-prime nucleotidase maps to chromosome 6q14-q21. (Abstract) Cytogenet. Cell Genet. 51: 968 only, 1989.
Boyle, J. M., Hey, Y., Geurts van Kessel, A., Fox, M. Assignment of ecto-5-prime-nucleotidase to human chromosome 6. Hum. Genet. 81: 88-92, 1988. [PubMed: 2848759] [Full Text: https://doi.org/10.1007/BF00283737]
Castrop, H., Huang, Y., Hashimoto, S., Mizel, D., Hansen, P., Theilig, F., Bachmann, S., Deng, C., Briggs, J., Schnermann, J. Impairment of tubuloglomerular feedback regulation of GFR in ecto-5-prime-nucleotidase/CD73-deficient mice. J. Clin. Invest. 114: 634-642, 2004. [PubMed: 15343381] [Full Text: https://doi.org/10.1172/JCI21851]
Fausther, M., Lavoie, E. G., Goree, J. R., Dranoff, J. A. An Elf2-like transcription factor acts as a repressor of the mouse ecto-5-prime-nucleotidase gene expression in hepatic myofibroblasts. Purinergic Signal. 13: 417-428, 2017. [PubMed: 28667437] [Full Text: https://doi.org/10.1007/s11302-017-9570-7]
Misumi, Y., Ogata, S., Ohkubo, K., Hirose, S., Ikehara, Y. Primary structure of human placental 5-prime-nucleotidase and identification of the glycolipid anchor in the mature form. Europ. J. Biochem. 191: 563-569, 1990. [PubMed: 2129526] [Full Text: https://doi.org/10.1111/j.1432-1033.1990.tb19158.x]
St. Hilaire, C., Ziegler, S. G., Markello, T. C., Brusco, A., Groden, C., Gill, F., Carlson-Donohoe, H., Lederman, R. J., Chen, M. Y., Yang, D., Siegenthaler, M. P., Arduino, C., and 9 others. NT5E mutations and arterial calcifications. New Eng. J. Med. 364: 432-442, 2011. [PubMed: 21288095] [Full Text: https://doi.org/10.1056/NEJMoa0912923]
Sun, D., Samuelson, L. C., Yang, T., Huang, Y., Paliege, A., Saunders, T., Briggs, J., Schnermann, J. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc. Nat. Acad. Sci. 98: 9983-9988, 2001. [PubMed: 11504952] [Full Text: https://doi.org/10.1073/pnas.171317998]