Alternative titles; symbols
HGNC Approved Gene Symbol: ENTPD1
SNOMEDCT: 726609005;
Cytogenetic location: 10q24.1 Genomic coordinates (GRCh38): 10:95,694,186-95,877,266 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.1 | Spastic paraplegia 64, autosomal recessive | 615683 | Autosomal recessive | 3 |
Plasma membrane-bound ectonucleoside trisphosphate diphosphohydrolases (ENTPDases), such as ENTPD1, modulate P2 receptor (see 600845) signaling by controlling extracellular nucleotide concentrations via nucleoside tri- and diphosphate hydrolysis (Munkonda et al., 2007).
Endothelial cells have the ability to regulate platelet activation, in part by the surface expression of ATP diphosphohydrolase (ATPDase; EC 3.6.1.5). ATPDase hydrolyzes extracellular ATP and ADP to AMP, which is further converted to adenosine by another enzyme, 5-prime nucleotidase. ADP is a powerful agonist for platelet recruitment and adhesion; adenosine is an antagonist of these processes. Kaczmarek et al. (1996) demonstrated that CD39, a B-cell activation marker previously characterized by Maliszewski et al. (1994), encodes vascular ATPDase. They isolated the cDNA of human ATPDase/CD39 by RT-PCR using RNA from human umbilical endothelial cells. They expressed this cDNA in COS-7 cells and confirmed that it is expressed on the cell surface, hydrolyzes both ATP and ADP, and inhibits platelet aggregation. CD39 was found to have both immunologic identity to, and functional characteristics of, vascular ATPDase. By Northern blot analysis, Chadwick and Frischauf (1998) found that CD39 is expressed as a major 3.2- and a minor 3.6-kb mRNA in several tissues. Additional bands were observed in a few tissues.
Adrian et al. (2000) analyzed the expression of several purinergic receptors, as well as CD39 and CD73 (NT5E; 129190), during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. CD39 expression was nearly undetectable in undifferentiated cells, but differentiation to either granulocytic or monocytic cells caused a strong increase in CD39 transcript. CD39 was moderately expressed in normal blood leukocytes.
By assaying cellular extracts of transfected COS-7 cells, Munkonda et al. (2007) showed that all P2 receptor antagonists tested, except for MRS2179, an AMP analog, inhibited human and mouse plasma membrane-bound ENTPDases, including ENTPD1.
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 (ADORA1; 102775) were essential for regulation of neuronal activity and animal behavior.
Gray et al. (1997) mapped the CD39 gene to a YAC contig of 10q24 between the genes for CYP2C (see 124020) and DNTT (187410).
Spastic Paraplegia 64, Autosomal Recessive
In affected members of 2 consanguineous families segregating autosomal recessive spastic paraplegia-64 (SPG64; 615683), Novarino et al. (2014) identified homozygosity for a missense mutation (G217R; 601752.0001) and a nonsense mutation (E181X; 601752.0002).
In 27 individuals with SPG64 from 17 unrelated families, Calame et al. (2022) identified biallelic mutations in the ENTPD1 gene. These included 12 novel mutations, of which 10 were associated with loss of function and predicted to result in nonsense-mediated decay or premature termination. Two other mutations were not associated with loss of function; one was a missense mutation and the other was a 2-bp deletion-insertion mutation, resulting in a single amino acid substitution. Four recurrent mutations were identified, including one found in 4 families (L370X; 601752.0003) and one found in 3 families (4-bp intronic deletion; 601752.0004). All but 1 of the mutations were absent from the gnomAD database; the exception was the L370X mutation, which was found in 2 heterozygotes of non-Finnish European descent. Functional studies showed that biallelic ENTPD1 mutations impaired ATP hydrolysis and reduced ENTPD1 expression.
Regulation of Immune Cell Levels
Orru et al. (2013) reported genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from 4 clustered Sardinian villages. Orru et al. (2013) first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean = 41%). Next, by assessing approximately 8.2 million variants that were identified and confirmed in an extended set of 2,870 individuals, Orru et al. (2013) found that 23 independent variants at 13 loci associated with at least 1 trait. The largest genetic effect was associated with a single intronic variant (rs11517041) of ENTPD1, encoding CD39, accounting for 60.8% of the phenotypic variation and 72% of the heritability of the levels of CD39+ activated CD4+ T-regulatory cells (p = 1.12 x 10(202)). Individuals homozygous for the T allele had the lowest number of CD39+ activated CD4+ T-regulatory cells. Heterozygotes were intermediate, and C homozygotes had the highest level, suggesting that this is a quantitative trait locus (QTL) for expression of this gene. A validation SNP in high linkage disequilibrium (r(2) = 0.993) achieved a p value of 7.05 x 10(-327). Orru et al. (2013) cited this mutation as a candidate mechanism in which cis-acting variation regulates the expression of a key marker in individual cells and therefore determines the number of cells expressing this molecule.
CD39 has been considered an important inhibitor of platelet activation. Unexpectedly, Enjyoji et al. (1999) found that Cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo, and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2y1 receptor (601167) desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in Cd39-deficient mice and in transplanted cardiac grafts. The data indicated the dual role for CD39 in modulating hemostasis and thrombotic reactions.
Langerhans cells (LC) are members of the dendritic cell (DC) family of antigen-presenting cells residing in the skin. Wolff and Winkelmann (1967) established that LC can be simply identified with light, rather than electron, microscopy using surface ATPase staining. Mizumoto et al. (2002) established that LC from CD39 -/- mice are not able to hydrolyze both ATP and ADP and that CD39 +/- mice have a diminished ability to effect ATP and ADP hydrolysis compared to wildtype mice. Histochemical, Northern, and Western blot analyses showed that CD39 is expressed in epidermal DC but not keratinocyte cell lines. CD39-deficient mice have amplified inflammatory responses to irritant chemicals, while heterozygous mice have intermediate responses compared to wildtype mice. On the other hand, CD39 -/- mice have similar responses to ultraviolet radiation and attenuated responses to contact allergens compared to heterozygotes and wildtype mice. Using a fluorescent contact allergen, Mizumoto et al. (2002) showed that the mutant mice LC are functional in their homing and phenotypic maturation but are less able to stimulate T cells, indicating that CD39 expression is required for optimal stimulation of hapten-reactive T cells in mice. CD39-deficient DC are unresponsive to ATP and are susceptible to cell death after prolonged exposure to ADP. Mizumoto et al. (2002) and Granstein (2002) proposed that if keratinocyte release of ATP and ADP occurs in response to all chemical irritants and if the magnitude of release correlates with the potency of the irritant, measurement of this release may be a useful in vitro method to assess the risk of cosmetics and other topical agents instead of animal testing.
In 2 affected brothers from a consanguineous family (family 1242) segregating spastic paraplegia-64 (SPG64; 615683), Novarino et al. (2014) identified homozygosity for a 649G-A transition in the ENTPD1 gene, resulting in a gly217-to-arg (G217R) substitution. This homozygous mutation was not found in unaffected family members.
In an affected brother and sister from a consanguineous family (family 1800) segregating spastic paraplegia-64 (SPG64; 615683), Novarino et al. (2014) identified homozygosity for a 719G-T transversion in the ENTPD1 gene, resulting in a glu181-to-ter (E181X) substitution. This homozygous mutation was not found in any unaffected family members.
In 8 patients from 4 unrelated consanguineous families (families 7, 10, 12, 17) with autosomal recessive spastic paraplegia-64 (SPG64; 615683), Calame et al. (2022) identified homozygosity for a c.1109T-A transversion (c.1109T-A, NM_001776.6) in exon 8 of the ENTPD1 gene, resulting in a leu370-to-ter (L370X) substitution. The mutation was found by trio exome sequencing and was present in gnomAD in 2 heterozygotes of non-Finnish European descent. Given that the mutation was found in 4 unrelated families, 1 from Poland and 3 from Iran, the authors suggested that leu370 could be a hotspot for mutation.
In 6 patients from 3 unrelated families (families 5, 6, 9) with autosomal recessive spastic paraplegia-64 (SPG64; 615683), Calame et al. (2022) identified a 4-bp deletion in intron 5 (c.574-6_574-3del, NM_001776.6) in the ENTPD1 gene, resulting in skipping of exon 6. Homozygosity for this variant was found in consanguineous families from Brazil and Portugal and in compound heterozygosity with a c.640del mutation (601752.0005), resulting in a frameshift and premature termination (Gly216GlufsTer75), in a nonconsanguineous family from Puerto Rico. Given that the mutation was found in unrelated families from countries with substantial Portuguese ancestry (Brazil and Portugal) suggests that these variants could be founder alleles from the Iberian Peninsula. The variant was not present in the gnomAD database.
For discussion of the 1-bp deletion at nucleotide 640 (c.640del, NM_001776.6) in the ENTPD1 gene, resulting in a frameshift and premature termination (Gly216GlufsTer75), that was found in compound heterozygous state in 2 patients in a Puerto Rican family (family 6) with autosomal recessive spastic paraplegia-64 (SPG64; 615683) by Calame et al. (2022), see 601752.0004.
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]
Calame, D. G., Herman, I., Maroofian, R., Marshall, A. E., Donis, K. C., Fatih, J. M., Mitani, T., Du, H., Grochowski, C. M., Sousa, S. B., Gijavanekar, C., Bakhtiari, S., and 53 others. Biallelic variants in the ectonucleotidase ENTPD1 cause a complex neurodevelopmental disorder with intellectual disability, distinct white matter abnormalities, and spastic paraplegia. Ann. Neurol. 92: 304-321, 2022. [PubMed: 35471564] [Full Text: https://doi.org/10.1002/ana.26381]
Chadwick, B. P., Frischauf, A.-M. The CD39-like gene family: identification of three new human members (CD39L2, CD39L3, and CD39L4), their murine homologues, and a member of the gene family from Drosophila melanogaster. Genomics 50: 357-367, 1998. [PubMed: 9676430] [Full Text: https://doi.org/10.1006/geno.1998.5317]
Enjyoji, K., Sevigny, J., Lin, Y., Frenette, P. S., Christie, P. D., am Esch, J. S., II, Imai, M., Edelberg, J. M., Rayburn, H., Lech, M., Beeler, D. L., Csizmadia, E., Wagner, D. D., Robson, S. C., Rosenberg, R. D. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nature Med. 5: 1010-1017, 1999. [PubMed: 10470077] [Full Text: https://doi.org/10.1038/12447]
Granstein, R. D. The skinny on CD39 in immunity and inflammation. Nature Med. 8: 336-338, 2002. [PubMed: 11927936] [Full Text: https://doi.org/10.1038/nm0402-336]
Gray, I. C., Fallowfield, J., Ford, S., Nobile, C., Volpi, E. V., Spurr, N. K. An integrated physical and genetic map spanning chromosome band 10q24. Genomics 43: 85-88, 1997. [PubMed: 9226376] [Full Text: https://doi.org/10.1006/geno.1997.4809]
Kaczmarek, E., Koziak, K., Sevigny, J., Siegel, J. B., Anrather, J., Beaudoin, A. R., Bach, F. H., Robson, S. C. Identification and characterization of CD39/vascular ATP diphosphohydrolase. J. Biol. Chem. 271: 33116-33122, 1996. [PubMed: 8955160] [Full Text: https://doi.org/10.1074/jbc.271.51.33116]
Maliszewski, C. R., Delespesse, G. L., Schoenborn, M. A., Armitage, R. J., Fanslow, W. C., Nakajima, T., Baker, E., Sutherland, G. R., Poindexter, K., Birks, C., Alpert, A., Friend, D., Gimpel, S. D., Gayle, R. B., III. The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization. J. Immun. 153: 3574-3583, 1994. [PubMed: 7930580]
Mizumoto, N., Kumamoto, T., Robson, S. C., Sevigny, J., Matsue, H., Enjyoji, K., Takashima, A. CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nature Med. 8: 358-365, 2002. [PubMed: 11927941] [Full Text: https://doi.org/10.1038/nm0402-358]
Munkonda, M. N., Kauffenstein, G., Kukulski, F., Levesque, S. A., Legendre, C., Pelletier, J., Lavoie, E. G., Lecka, J., Sevigny, J. Inhibition of human and mouse plasma membrane bound NTPDases by P2 receptor antagonists. Biochem. Pharm. 74: 1524-1534, 2007. [PubMed: 17727821] [Full Text: https://doi.org/10.1016/j.bcp.2007.07.033]
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J. L., 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]
Orru, V., Steri, M., Sole, G., Sidore, C., Virdis, F., Dei, M., Lai, S., Zoledziewska, M., Busonero, F., Mulas, A., Floris, M., Mentzen, W. I., and 40 others. Genetic variants regulating immune cell levels in health and disease. Cell 155: 242-256, 2013. [PubMed: 24074872] [Full Text: https://doi.org/10.1016/j.cell.2013.08.041]
Wolff, K,., Winkelmann, R. K. Ultrastructural localization of nucleoside triphosphatase in Langerhans cells. J. Invest. Derm. 48: 50-54, 1967. [PubMed: 4289467] [Full Text: https://doi.org/10.1038/jid.1967.8]