Alternative titles; symbols
HGNC Approved Gene Symbol: PNP
SNOMEDCT: 60743005; ICD10CM: D81.5;
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:20,469,406-20,477,089 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Immunodeficiency due to purine nucleoside phosphorylase deficiency | 613179 | Autosomal recessive | 3 |
The PNP gene encodes purine nucleoside phosphorylase (EC 2.4.2.1), an enzyme that catalyzes the reversible phosphorolysis of the purine nucleosides and deoxynucleosides inosine, guanosine, deoxyinosine, and deoxyguanosine (Williams et al., 1984).
Zannis et al. (1978) and Williams et al. (1984) demonstrated that human PNP is a symmetric trimer composed of 3 identical 32,153-Da subunits, each with a substrate-binding site. PNP encodes a deduced protein of 289 amino acids.
From the findings in somatic cell hybridization studies, nucleoside phosphorylase is known to be determined by a structural locus on chromosome 14. In a classic experiment using the KOP (Kirby-Opitz-Pallister) cell line carrying an X;14 translocation (GM73 and GM74), Ricciuti and Ruddle (1973) showed that the PNP locus is on chromosome 14 (and G6PD (305900) on distal Xq). In hybridization experiments with t(X;14)(p22;q21), Francke et al. (1976) found that the PNP locus is proximal to 14q22. Using gene dosage effect and 4 cases of different partial trisomy of chromosome 14, George and Francke (1976) narrowed the assignment of PNP to the region 14q11-q21. Frecker et al. (1978) presented results from gene dosage studies consistent with assignment of the PNP locus to band 14q13. Allderdice et al. (1978) investigated spreading of inactivation in the KOP translocation originally used in mapping PNP to 14q. Remes et al. (1984) presented additional deletion mapping data that they interpreted, in the light of earlier findings, as narrowing the SRO for PNP to 14q12.00-q13.105. The location was placed at 14q13.1. The evidence of Harper et al. (1988) indicated that the PNP gene is located centromeric to TCRA (see 186880). HGM10 concluded that PNP is located in the 14q11.2 band.
Edwards et al. (1971) described electrophoretic variants of nucleoside phosphorylase. Family studies indicated autosomal codominant inheritance of the variants.
In a patient with nucleoside phosphorylase deficiency (613179), Williams et al. (1987) identified a homozygous mutation in the PNP gene (E89K; 164050.0001).
Aust et al. (1992) identified compound heterozygosity for 2 mutations in the PNP gene (D128G, 164050.0003; R234P, 164050.0004) in a patient with nucleoside phosphorylase deficiency.
In a patient with PNP deficiency, Dalal et al. (2001) identified compound heterozygosity for 2 mutations in the PNP gene (164050.0009; 164050.0010).
By male germ cell mutagenesis, Snyder et al. (1997) recovered 3 point mutations in the Pnp gene. These were, in order of increasing order of severity of enzyme deficiency and phenotype, met87 to lys, ala228 to thr, and trp16 to arg. A marked decline in total cell numbers per thymus occurred between 2 and 3 months for the 2 more severe mutants (35% and 52%, respectively) and by 8 months for the least severe mutation. Spleen lymphocyte Thy-1(+) cells were reduced by 50% and spleen lymphocyte response to T-cell mitogen and interleukin-2 was reduced by 80%. The Pnp-deficient mouse exhibited age-dependent progressive perturbations in thymocyte differentiation, reduced numbers of thymocytes, and reduced splenic T-cell numbers and response. The progressive T-cell deficit was similar to that observed in the human disorder.
In a patient with nucleoside phosphorylase deficiency (613179), Williams et al. (1987) identified a homozygous 265G-A transition in exon 3 of the PNP gene, resulting in a glu89-to-lys (E89K) substitution. The patient was born of consanguineous parents.
In a patient with nucleoside phosphorylase deficiency (613179), Markert and Barrett (1989) identified compound heterozygosity for 2 mutations in the PNP gene: a 520G-C transversion, resulting in an ala174-to-pro (A174P) substitution, and E89K (164050.0001).
Markert (1992) indicated that this mutant protein had normal function when expressed in COS cells. However, it was possible that the mutation may have caused an abnormality in protein stability or other posttranscriptional stages.
In a patient with nucleoside phosphorylase deficiency (613179), Aust et al. (1992) found compound heterozygosity for an asp128-to-gly (D128G) substitution in the maternal allele and an arg234-to-pro mutation (R234P; 164050.0004) in the paternal allele. In addition, the patient was homozygous for a ser51-to-gly substitution (S51G; 164050.0005), which is a polymorphism. In order to prove that the 2 mutations were responsible for the disease state, each of the 3 mutations was constructed separately by site-directed mutagenesis of the normal PNP cDNA, and each was transiently expressed in COS cells. Lysates from cells transfected with the allele carrying the substitution at amino acid 51 retained both function and immunoreactivity. Lysates from cells transfected with alleles carrying a substitution at either amino acid 128 or amino acid 234 contained immunoreactive material but had no detectable human enzyme activity.
For discussion of the arg234-to-pro (R234P) mutation in the PNP gene that was found in compound heterozygous state in a patient with nucleoside phosphorylase deficiency (613179) by Aust et al. (1992), see 164050.0003.
Markert et al. (1997) found the R234P mutation in 3 unrelated patients, making this the most common mutation reported in PNP deficiency to that time.
See 164050.0003 and Aust et al. (1992).
Pannicke et al. (1996) studied a female patient with severe combined immunodeficiency (613179) and found compound heterozygosity for 2 mutations in the PNP gene: an A-to-G transition in exon 5, resulting in a tyr192-to-cys (Y192C) substitution, and a 1-bp deletion in exon 6 (164050.0007), resulting in premature termination. Both PNP mutations affected major structural motifs of the protein and resulted in posttranslational instability of the enzyme. The patient showed the first signs of developmental delay at the age of 6 months and at 20 months recurrent bronchitis and episodes of sepsis pneumonia began. At the age of 24 months, she presented with persistent diarrhea. PNP deficiency was diagnosed at 2.5 years when she developed a large lymphoma due to EBV infection. After chemotherapy, a haploidentical maternal bone marrow transplantation was performed at the age of 35 months. However, the patient died from a severe systemic adenovirus infection at 36 months.
For discussion of the 1-bp deletion in exon 6 of the PNP gene that was found in compound heterozygous state in a patient with severe combined immunodeficiency (613179) by Pannicke et al. (1996), see 164050.0006.
In a patient with nucleoside phosphorylase deficiency (613179), Sasaki et al. (1998) demonstrated homozygosity for an arg24-to-ter (R24X) substitution in exon 2. Both parents were heterozygous for the mutation. The patient, a 3-year-old boy, was the third of 3 children born of a second-cousin marriage. After birth, the patient had recurrent urinary tract infections. He showed hypouricemia, lymphopenia, an immunologic disorder in T-cell function, a low level of plasma hypoxanthine, and a high level of plasma inosine.
In a case of PNP deficiency (613179), Dalal et al. (2001) found compound heterozygosity for mutations in the PNP gene, a maternally derived arg58-to-ter (R58X) mutation and a paternally derived splice site mutation. The maternal allele showed a 172C-T transition in exon 2, resulting in R58X. The paternally-derived allele showed complete absence of exon 3 with precise joining of exon 2 to exon 4, due to a G-to-A transition in intron 3 at position +1 (see 164050.0010). A frameshift resulted from a change in the reading frame because of the split codon, which was GTG (val) in the normal bridge between exon 2 and exon 3, but became GGT (gly) in the bridge between exon 2 and exon 4. Translation of the mutant paternally-derived allele terminated after 89 amino acids, 29 residues downstream of the exon 2-exon 4 junction.
For discussion of the splice site mutation in the PNP gene that was found in compound heterozygous state in a patient with nucleoside phosphorylase deficiency (613179) by Dalal et al. (2001), see 164050.0009.
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Allderdice, P. W., Miller, O. J., Miller, D. A., Klinger, H. P. Spreading of inactivation in an (X;14) translocation. Am. J. Med. Genet. 2: 233-240, 1978. [PubMed: 263441] [Full Text: https://doi.org/10.1002/ajmg.1320020304]
Aust, M. R., Andrews, L. G., Barrett, M. J., Norby-Slycord, C. J., Markert, M. L. Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency. Am. J. Hum. Genet. 51: 763-772, 1992. [PubMed: 1384322]
Dalal, I., Grunebaum, E., Cohen, A., Roifman, C. M. Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient patient. Clin. Genet. 59: 430-437, 2001. [PubMed: 11453975] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.590608.x]
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Edwards, Y. H., Hopkinson, D. A., Harris, H. Inherited variants of human nucleoside phosphorylase. Ann. Hum. Genet. 34: 395-408, 1971. [PubMed: 5579411] [Full Text: https://doi.org/10.1111/j.1469-1809.1971.tb00252.x]
Francke, U., Busby, N., Shaw, D., Hansen, S., Brown, M. G. Intrachromosomal gene mapping in man: assignment of nucleoside phosphorylase to region 14cen-to-14q21 by interspecific hybridization of cells with a t(X;14)(p22;q21) translocation. Somat. Cell Genet. 2: 27-40, 1976. [PubMed: 829289] [Full Text: https://doi.org/10.1007/BF01539240]
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George, D. L., Francke, U. Gene dose effect: regional mapping of human nucleoside phosphorylase on chromosome 14. Science 194: 851-852, 1976. [PubMed: 824731] [Full Text: https://doi.org/10.1126/science.824731]
Harper, K., Mattei, M.-G., Simon, D., Suzan, M., Guenet, J.-L., Haddad, P., Sasportes, M., Golstein, P. Proximity of the CTLA-1 serine esterase and Tcr(alpha) loci in mouse and man. Immunogenetics 28: 439-444, 1988. [PubMed: 3182016] [Full Text: https://doi.org/10.1007/BF00355376]
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Markert, M. L., Barrett, M. J. Point mutations causing purine nucleoside phosphorylase deficiency in a child with immunodeficiency. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A205 only, 1989.
Markert, M. L., Finkel, B. D., McLaughlin, T. M., Watson, T. J., Collard, H. R., McMahon, C. P., Andrews, L. G., Barrett, M. J., Ward, F. E. Mutations in purine nucleoside phosphorylase deficiency. Hum. Mutat. 9: 118-121, 1997. [PubMed: 9067751] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)9:2<118::AID-HUMU3>3.0.CO;2-5]
Pannicke, U., Tuchschmid, P., Friedrich, W., Bartram, C. R., Schwarz, K. Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient. Hum. Genet. 98: 706-709, 1996. [PubMed: 8931706] [Full Text: https://doi.org/10.1007/s004390050290]
Remes, G. M., Fisher, R. A., Hackel, E., Cousineau, A. J., Higgins, J. V. SRO refinement for nucleoside phosphorylase by deletion mapping of chromosome 14. (Abstract) Cytogenet. Cell Genet. 37: 568 only, 1984.
Ricciuti, F., Ruddle, F. H. Assignment of nucleoside phosphorylase to D-14 and localization of X-linked loci in man by somatic cell genetics. Nature N.B. 241: 180-182, 1973. [PubMed: 4512579] [Full Text: https://doi.org/10.1038/newbio241180a0]
Sasaki, Y., Iseki, M., Yamaguchi, S., Kurosawa, Y., Yamamoto, T., Moriwaki, Y., Kenri, T., Sasaki, T., Yamashita, R. Direct evidence of autosomal recessive inheritance of arg24 to termination codon in purine nucleoside phosphorylase gene in a family with a severe combined immunodeficiency patient. Hum. Genet. 103: 81-85, 1998. [PubMed: 9737781] [Full Text: https://doi.org/10.1007/s004390050787]
Snyder, F. F., Jenuth, J. P., Mably, E. R., Mangat, R. K. Point mutations at the purine nucleoside phosphorylase locus impair thymocyte differentiation in the mouse. Proc. Nat. Acad. Sci. 94: 2522-2527, 1997. [PubMed: 9122228] [Full Text: https://doi.org/10.1073/pnas.94.6.2522]
Williams, S. R., Gekeler, V., McIvor, R. S., Martin, D. W., Jr. A human purine nucleoside phosphorylase deficiency caused by a single base change. J. Biol. Chem. 262: 2332-2338, 1987. [PubMed: 3029074]
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Zannis, V., Doyle, D., Martin, D. W., Jr. Purification and characterization of human erythrocyte purine nucleoside phosphorylase and its subunits. J. Biol. Chem. 253: 504-510, 1978. [PubMed: 412851]