Full text data of PNP
PNP
(NP)
[Confidence: high (present in two of the MS resources)]
Purine nucleoside phosphorylase; PNP; 2.4.2.1 (Inosine phosphorylase; Inosine-guanosine phosphorylase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Purine nucleoside phosphorylase; PNP; 2.4.2.1 (Inosine phosphorylase; Inosine-guanosine phosphorylase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00017672
IPI00017672 Hypothetical protein FLJ25678 nucloside and nucleic acid metabolism, Inosine phosphorylase, defects: T-cell immunodeficiency soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00017672 Hypothetical protein FLJ25678 nucloside and nucleic acid metabolism, Inosine phosphorylase, defects: T-cell immunodeficiency soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P00491
ID PNPH_HUMAN Reviewed; 289 AA.
AC P00491; B2R8S5; D3DS00; Q15160; Q5PZ03;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-MAY-2006, sequence version 2.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Purine nucleoside phosphorylase;
DE Short=PNP;
DE EC=2.4.2.1;
DE AltName: Full=Inosine phosphorylase;
DE AltName: Full=Inosine-guanosine phosphorylase;
GN Name=PNP; Synonyms=NP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-51.
RX PubMed=6087295; DOI=10.1093/nar/12.14.5779;
RA Williams S.R., Goddard J.M., Martin D.W. Jr.;
RT "Human purine nucleoside phosphorylase cDNA sequence and genomic clone
RT characterization.";
RL Nucleic Acids Res. 12:5779-5787(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PNPD LYS-89, AND VARIANT
RP SER-51.
RX PubMed=3029074;
RA Williams S.R., Gekeler V., McIvor R.S., Martin D.W. Jr.;
RT "A human purine nucleoside phosphorylase deficiency caused by a single
RT base change.";
RL J. Biol. Chem. 262:2332-2338(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-51.
RX PubMed=12928150;
RA Yu L., Kalla K., Guthrie E., Vidrine A., Klimecki W.T.;
RT "Genetic variation in genes associated with arsenic metabolism:
RT glutathione S-transferase omega 1-1 and purine nucleoside
RT phosphorylase polymorphisms in European and indigenous Americans.";
RL Environ. Health Perspect. 111:1421-1427(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-51.
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 1-22; 42-58; 68-76; 96-148; 212-229; 235-265 AND
RP 271-287, ACETYLATION AT MET-1, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (FEB-2006) to UniProtKB.
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=22509282; DOI=10.1371/journal.pone.0034237;
RA von Lohneysen K., Scott T.M., Soldau K., Xu X., Friedman J.S.;
RT "Assessment of the red cell proteome of young patients with
RT unexplained hemolytic anemia by two-dimensional differential in-gel
RT electrophoresis (DIGE).";
RL PLoS ONE 7:E34237-E34237(2012).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS), AND FUNCTION.
RX PubMed=2104852;
RA Ealick S.E., Rule S.A., Carter D.C., Greenhough T.J., Babu Y.S.,
RA Cook W.J., Habash J., Helliwell J.R., Stoeckler J.D., Parks R.E. Jr.,
RA Chen S.-F., Bugg C.E.;
RT "Three-dimensional structure of human erythrocytic purine nucleoside
RT phosphorylase at 3.2-A resolution.";
RL J. Biol. Chem. 265:1812-1820(1990).
RN [13]
RP VARIANT SER-51, AND VARIANTS PNPD GLY-128 AND PRO-234.
RX PubMed=1384322;
RA Aust M.R., Andrews L.G., Barrett M.J., Norby-Slycord C.J.,
RA Markert M.L.;
RT "Molecular analysis of mutations in a patient with purine nucleoside
RT phosphorylase deficiency.";
RL Am. J. Hum. Genet. 51:763-772(1992).
RN [14]
RP VARIANT PNPD CYS-192.
RX PubMed=8931706; DOI=10.1007/s004390050290;
RA Pannicke U., Tuchschmid P., Friedrich W., Bartram C.R., Schwarz K.;
RT "Two novel missense and frameshift mutations in exons 5 and 6 of the
RT purine nucleoside phosphorylase (PNP) gene in a severe combined
RT immunodeficiency (SCID) patient.";
RL Hum. Genet. 98:706-709(1996).
CC -!- FUNCTION: The purine nucleoside phosphorylases catalyze the
CC phosphorolytic breakdown of the N-glycosidic bond in the beta-
CC (deoxy)ribonucleoside molecules, with the formation of the
CC corresponding free purine bases and pentose-1-phosphate.
CC -!- CATALYTIC ACTIVITY: Purine nucleoside + phosphate = purine +
CC alpha-D-ribose 1-phosphate.
CC -!- PATHWAY: Purine metabolism; purine nucleoside salvage.
CC -!- SUBUNIT: Homotrimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton (By similarity).
CC Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in red blood cells; overexpressed in
CC red blood cells (cytoplasm) of patients with hereditary non-
CC spherocytic hemolytic anemia of unknown etiology.
CC -!- DISEASE: Purine nucleoside phosphorylase deficiency (PNPD)
CC [MIM:613179]: A disorder that interrupts both the catabolism of
CC inosine into hypoxanthine and guanosine into guanine, and leads to
CC the accumulation of guanosine, inosine, and their deoxified by-
CC products. The main clinical presentation is recurrent infections
CC due to severe T-cell immunodeficiency. Some patients also have
CC neurologic impairment. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PNP/MTAP phosphorylase family.
CC -!- WEB RESOURCE: Name=NPbase; Note=NP mutation db;
CC URL="http://bioinf.uta.fi/NPbase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NP";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X00737; CAA25320.1; -; mRNA.
DR EMBL; M13953; AAA36460.1; -; Genomic_DNA.
DR EMBL; J02672; AAA36460.1; JOINED; Genomic_DNA.
DR EMBL; M13951; AAA36460.1; JOINED; Genomic_DNA.
DR EMBL; M13952; AAA36460.1; JOINED; Genomic_DNA.
DR EMBL; AY817667; AAV68044.1; -; Genomic_DNA.
DR EMBL; AK313490; BAG36272.1; -; mRNA.
DR EMBL; CR407607; CAG28535.1; -; mRNA.
DR EMBL; CH471078; EAW66458.1; -; Genomic_DNA.
DR EMBL; CH471078; EAW66459.1; -; Genomic_DNA.
DR EMBL; BC104206; AAI04207.1; -; mRNA.
DR EMBL; BC104207; AAI04208.1; -; mRNA.
DR EMBL; BC106074; AAI06075.1; -; mRNA.
DR PIR; A00578; PHHUPN.
DR RefSeq; NP_000261.2; NM_000270.3.
DR UniGene; Hs.75514; -.
DR PDB; 1M73; X-ray; 2.30 A; E=2-289.
DR PDB; 1PF7; X-ray; 2.60 A; E=1-289.
DR PDB; 1PWY; X-ray; 2.80 A; E=2-289.
DR PDB; 1RCT; X-ray; 2.80 A; E=2-289.
DR PDB; 1RFG; X-ray; 2.90 A; E=2-289.
DR PDB; 1RR6; X-ray; 2.50 A; A=1-289.
DR PDB; 1RSZ; X-ray; 2.20 A; A=1-289.
DR PDB; 1RT9; X-ray; 2.30 A; A=1-289.
DR PDB; 1ULA; X-ray; 2.75 A; A=1-289.
DR PDB; 1ULB; X-ray; 2.75 A; A=1-289.
DR PDB; 1V2H; X-ray; 2.70 A; E=2-289.
DR PDB; 1V3Q; X-ray; 2.80 A; E=2-289.
DR PDB; 1V41; X-ray; 2.85 A; E=2-289.
DR PDB; 1V45; X-ray; 2.86 A; E=2-289.
DR PDB; 1YRY; X-ray; 2.80 A; E=1-289.
DR PDB; 2A0W; X-ray; 2.28 A; A=1-289.
DR PDB; 2A0X; X-ray; 2.28 A; A=1-289.
DR PDB; 2A0Y; X-ray; 2.28 A; A=1-289.
DR PDB; 2OC4; X-ray; 2.59 A; A=1-289.
DR PDB; 2OC9; X-ray; 2.59 A; A=1-289.
DR PDB; 2ON6; X-ray; 2.50 A; A=1-289.
DR PDB; 2Q7O; X-ray; 2.90 A; E=1-289.
DR PDB; 3BGS; X-ray; 2.10 A; A=1-289.
DR PDB; 3D1V; X-ray; 2.70 A; A=1-289.
DR PDB; 3GB9; X-ray; 2.30 A; A/B/C=1-289.
DR PDB; 3GGS; X-ray; 2.52 A; A/B/C=1-289.
DR PDB; 3INY; X-ray; 2.75 A; A=1-289.
DR PDB; 3K8O; X-ray; 2.40 A; E/Q/S/T/U/Y=1-289.
DR PDB; 3K8Q; X-ray; 2.50 A; A=1-289.
DR PDB; 3PHB; X-ray; 2.30 A; E/Q/S/T/U/Y=1-289.
DR PDB; 4EAR; X-ray; 1.70 A; A/B/C=1-289.
DR PDB; 4EB8; X-ray; 2.30 A; A/B/C=1-289.
DR PDB; 4ECE; X-ray; 2.60 A; A/B/C/D/E/F=1-289.
DR PDB; 4GKA; X-ray; 2.20 A; A/B/C/D/E/F=1-289.
DR PDBsum; 1M73; -.
DR PDBsum; 1PF7; -.
DR PDBsum; 1PWY; -.
DR PDBsum; 1RCT; -.
DR PDBsum; 1RFG; -.
DR PDBsum; 1RR6; -.
DR PDBsum; 1RSZ; -.
DR PDBsum; 1RT9; -.
DR PDBsum; 1ULA; -.
DR PDBsum; 1ULB; -.
DR PDBsum; 1V2H; -.
DR PDBsum; 1V3Q; -.
DR PDBsum; 1V41; -.
DR PDBsum; 1V45; -.
DR PDBsum; 1YRY; -.
DR PDBsum; 2A0W; -.
DR PDBsum; 2A0X; -.
DR PDBsum; 2A0Y; -.
DR PDBsum; 2OC4; -.
DR PDBsum; 2OC9; -.
DR PDBsum; 2ON6; -.
DR PDBsum; 2Q7O; -.
DR PDBsum; 3BGS; -.
DR PDBsum; 3D1V; -.
DR PDBsum; 3GB9; -.
DR PDBsum; 3GGS; -.
DR PDBsum; 3INY; -.
DR PDBsum; 3K8O; -.
DR PDBsum; 3K8Q; -.
DR PDBsum; 3PHB; -.
DR PDBsum; 4EAR; -.
DR PDBsum; 4EB8; -.
DR PDBsum; 4ECE; -.
DR PDBsum; 4GKA; -.
DR ProteinModelPortal; P00491; -.
DR SMR; P00491; 2-289.
DR DIP; DIP-50406N; -.
DR IntAct; P00491; 7.
DR MINT; MINT-1375849; -.
DR STRING; 9606.ENSP00000354532; -.
DR BindingDB; P00491; -.
DR ChEMBL; CHEMBL4338; -.
DR DrugBank; DB00787; Aciclovir.
DR DrugBank; DB00242; Cladribine.
DR DrugBank; DB01033; Mercaptopurine.
DR PhosphoSite; P00491; -.
DR DMDM; 108935929; -.
DR OGP; P00491; -.
DR PaxDb; P00491; -.
DR PRIDE; P00491; -.
DR Ensembl; ENST00000361505; ENSP00000354532; ENSG00000198805.
DR GeneID; 4860; -.
DR KEGG; hsa:4860; -.
DR UCSC; uc001vxo.4; human.
DR CTD; 4860; -.
DR GeneCards; GC14P021021; -.
DR HGNC; HGNC:7892; PNP.
DR HPA; HPA001625; -.
DR MIM; 164050; gene.
DR MIM; 613179; phenotype.
DR neXtProt; NX_P00491; -.
DR Orphanet; 760; Purine nucleoside phosphorylase deficiency.
DR PharmGKB; PA31694; -.
DR eggNOG; COG0005; -.
DR HOVERGEN; HBG002460; -.
DR KO; K03783; -.
DR OMA; ITDHINY; -.
DR PhylomeDB; P00491; -.
DR BioCyc; MetaCyc:HS02151-MONOMER; -.
DR BRENDA; 2.4.2.1; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P00491; -.
DR SignaLink; P00491; -.
DR UniPathway; UPA00606; -.
DR ChiTaRS; PNP; human.
DR EvolutionaryTrace; P00491; -.
DR GeneWiki; Purine_nucleoside_phosphorylase; -.
DR GenomeRNAi; 4860; -.
DR NextBio; 18722; -.
DR PRO; PR:P00491; -.
DR ArrayExpress; P00491; -.
DR Bgee; P00491; -.
DR CleanEx; HS_NP; -.
DR Genevestigator; P00491; -.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0008144; F:drug binding; IDA:UniProtKB.
DR GO; GO:0001882; F:nucleoside binding; IDA:UniProtKB.
DR GO; GO:0042301; F:phosphate ion binding; IDA:UniProtKB.
DR GO; GO:0002060; F:purine nucleobase binding; IDA:UniProtKB.
DR GO; GO:0004731; F:purine-nucleoside phosphorylase activity; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; IMP:UniProtKB.
DR GO; GO:0006148; P:inosine catabolic process; IDA:MGI.
DR GO; GO:0070970; P:interleukin-2 secretion; IMP:UniProtKB.
DR GO; GO:0034356; P:NAD biosynthesis via nicotinamide riboside salvage pathway; IGI:UniProtKB.
DR GO; GO:0006738; P:nicotinamide riboside catabolic process; IDA:UniProtKB.
DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IDA:MGI.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IDA:MGI.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006195; P:purine nucleotide catabolic process; TAS:Reactome.
DR GO; GO:0043101; P:purine-containing compound salvage; TAS:Reactome.
DR GO; GO:0042493; P:response to drug; IDA:UniProtKB.
DR GO; GO:0034418; P:urate biosynthetic process; IDA:MGI.
DR Gene3D; 3.40.50.1580; -; 1.
DR InterPro; IPR000845; Nucleoside_phosphorylase_d.
DR InterPro; IPR001369; PNP/MTAP.
DR InterPro; IPR011270; Pur_Nuc_Pase_Ino/Guo-sp.
DR InterPro; IPR011268; Purine_phosphorylase.
DR InterPro; IPR018099; Purine_phosphorylase-2_CS.
DR PANTHER; PTHR11904; PTHR11904; 1.
DR PANTHER; PTHR11904:SF9; PTHR11904:SF9; 1.
DR Pfam; PF01048; PNP_UDP_1; 1.
DR PIRSF; PIRSF000477; PurNPase; 1.
DR TIGRFAMs; TIGR01700; PNPH; 1.
DR TIGRFAMs; TIGR01697; PNPH-PUNA-XAPA; 1.
DR PROSITE; PS01240; PNP_MTAP_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Glycosyltransferase;
KW Polymorphism; Reference proteome; Transferase.
FT CHAIN 1 289 Purine nucleoside phosphorylase.
FT /FTId=PRO_0000184536.
FT MOD_RES 1 1 N-acetylmethionine.
FT VARIANT 51 51 G -> S (in dbSNP:rs1049564).
FT /FTId=VAR_002243.
FT VARIANT 89 89 E -> K (in PNPD).
FT /FTId=VAR_002244.
FT VARIANT 128 128 D -> G (in PNPD).
FT /FTId=VAR_002245.
FT VARIANT 174 174 A -> P (in PNPD).
FT /FTId=VAR_002246.
FT VARIANT 192 192 Y -> C (in PNPD).
FT /FTId=VAR_010653.
FT VARIANT 234 234 R -> P (in PNPD).
FT /FTId=VAR_002247.
FT HELIX 7 20
FT STRAND 26 31
FT HELIX 36 41
FT STRAND 43 49
FT HELIX 50 52
FT STRAND 53 55
FT HELIX 62 65
FT STRAND 67 73
FT STRAND 76 83
FT HELIX 87 89
FT HELIX 93 96
FT HELIX 98 106
FT STRAND 110 119
FT STRAND 121 123
FT STRAND 129 137
FT HELIX 138 141
FT TURN 153 155
FT TURN 163 166
FT HELIX 168 179
FT TURN 180 182
FT STRAND 188 194
FT STRAND 197 199
FT HELIX 203 211
FT STRAND 215 221
FT HELIX 222 230
FT STRAND 234 244
FT STRAND 248 250
FT HELIX 257 266
FT HELIX 268 280
FT TURN 285 287
SQ SEQUENCE 289 AA; 32118 MW; 91622FB1D26479D3 CRC64;
MENGYTYEDY KNTAEWLLSH TKHRPQVAII CGSGLGGLTD KLTQAQIFDY GEIPNFPRST
VPGHAGRLVF GFLNGRACVM MQGRFHMYEG YPLWKVTFPV RVFHLLGVDT LVVTNAAGGL
NPKFEVGDIM LIRDHINLPG FSGQNPLRGP NDERFGDRFP AMSDAYDRTM RQRALSTWKQ
MGEQRELQEG TYVMVAGPSF ETVAECRVLQ KLGADAVGMS TVPEVIVARH CGLRVFGFSL
ITNKVIMDYE SLEKANHEEV LAAGKQAAQK LEQFVSILMA SIPLPDKAS
//
ID PNPH_HUMAN Reviewed; 289 AA.
AC P00491; B2R8S5; D3DS00; Q15160; Q5PZ03;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-MAY-2006, sequence version 2.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Purine nucleoside phosphorylase;
DE Short=PNP;
DE EC=2.4.2.1;
DE AltName: Full=Inosine phosphorylase;
DE AltName: Full=Inosine-guanosine phosphorylase;
GN Name=PNP; Synonyms=NP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-51.
RX PubMed=6087295; DOI=10.1093/nar/12.14.5779;
RA Williams S.R., Goddard J.M., Martin D.W. Jr.;
RT "Human purine nucleoside phosphorylase cDNA sequence and genomic clone
RT characterization.";
RL Nucleic Acids Res. 12:5779-5787(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PNPD LYS-89, AND VARIANT
RP SER-51.
RX PubMed=3029074;
RA Williams S.R., Gekeler V., McIvor R.S., Martin D.W. Jr.;
RT "A human purine nucleoside phosphorylase deficiency caused by a single
RT base change.";
RL J. Biol. Chem. 262:2332-2338(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-51.
RX PubMed=12928150;
RA Yu L., Kalla K., Guthrie E., Vidrine A., Klimecki W.T.;
RT "Genetic variation in genes associated with arsenic metabolism:
RT glutathione S-transferase omega 1-1 and purine nucleoside
RT phosphorylase polymorphisms in European and indigenous Americans.";
RL Environ. Health Perspect. 111:1421-1427(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-51.
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 1-22; 42-58; 68-76; 96-148; 212-229; 235-265 AND
RP 271-287, ACETYLATION AT MET-1, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (FEB-2006) to UniProtKB.
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=22509282; DOI=10.1371/journal.pone.0034237;
RA von Lohneysen K., Scott T.M., Soldau K., Xu X., Friedman J.S.;
RT "Assessment of the red cell proteome of young patients with
RT unexplained hemolytic anemia by two-dimensional differential in-gel
RT electrophoresis (DIGE).";
RL PLoS ONE 7:E34237-E34237(2012).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS), AND FUNCTION.
RX PubMed=2104852;
RA Ealick S.E., Rule S.A., Carter D.C., Greenhough T.J., Babu Y.S.,
RA Cook W.J., Habash J., Helliwell J.R., Stoeckler J.D., Parks R.E. Jr.,
RA Chen S.-F., Bugg C.E.;
RT "Three-dimensional structure of human erythrocytic purine nucleoside
RT phosphorylase at 3.2-A resolution.";
RL J. Biol. Chem. 265:1812-1820(1990).
RN [13]
RP VARIANT SER-51, AND VARIANTS PNPD GLY-128 AND PRO-234.
RX PubMed=1384322;
RA Aust M.R., Andrews L.G., Barrett M.J., Norby-Slycord C.J.,
RA Markert M.L.;
RT "Molecular analysis of mutations in a patient with purine nucleoside
RT phosphorylase deficiency.";
RL Am. J. Hum. Genet. 51:763-772(1992).
RN [14]
RP VARIANT PNPD CYS-192.
RX PubMed=8931706; DOI=10.1007/s004390050290;
RA Pannicke U., Tuchschmid P., Friedrich W., Bartram C.R., Schwarz K.;
RT "Two novel missense and frameshift mutations in exons 5 and 6 of the
RT purine nucleoside phosphorylase (PNP) gene in a severe combined
RT immunodeficiency (SCID) patient.";
RL Hum. Genet. 98:706-709(1996).
CC -!- FUNCTION: The purine nucleoside phosphorylases catalyze the
CC phosphorolytic breakdown of the N-glycosidic bond in the beta-
CC (deoxy)ribonucleoside molecules, with the formation of the
CC corresponding free purine bases and pentose-1-phosphate.
CC -!- CATALYTIC ACTIVITY: Purine nucleoside + phosphate = purine +
CC alpha-D-ribose 1-phosphate.
CC -!- PATHWAY: Purine metabolism; purine nucleoside salvage.
CC -!- SUBUNIT: Homotrimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton (By similarity).
CC Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in red blood cells; overexpressed in
CC red blood cells (cytoplasm) of patients with hereditary non-
CC spherocytic hemolytic anemia of unknown etiology.
CC -!- DISEASE: Purine nucleoside phosphorylase deficiency (PNPD)
CC [MIM:613179]: A disorder that interrupts both the catabolism of
CC inosine into hypoxanthine and guanosine into guanine, and leads to
CC the accumulation of guanosine, inosine, and their deoxified by-
CC products. The main clinical presentation is recurrent infections
CC due to severe T-cell immunodeficiency. Some patients also have
CC neurologic impairment. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PNP/MTAP phosphorylase family.
CC -!- WEB RESOURCE: Name=NPbase; Note=NP mutation db;
CC URL="http://bioinf.uta.fi/NPbase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NP";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X00737; CAA25320.1; -; mRNA.
DR EMBL; M13953; AAA36460.1; -; Genomic_DNA.
DR EMBL; J02672; AAA36460.1; JOINED; Genomic_DNA.
DR EMBL; M13951; AAA36460.1; JOINED; Genomic_DNA.
DR EMBL; M13952; AAA36460.1; JOINED; Genomic_DNA.
DR EMBL; AY817667; AAV68044.1; -; Genomic_DNA.
DR EMBL; AK313490; BAG36272.1; -; mRNA.
DR EMBL; CR407607; CAG28535.1; -; mRNA.
DR EMBL; CH471078; EAW66458.1; -; Genomic_DNA.
DR EMBL; CH471078; EAW66459.1; -; Genomic_DNA.
DR EMBL; BC104206; AAI04207.1; -; mRNA.
DR EMBL; BC104207; AAI04208.1; -; mRNA.
DR EMBL; BC106074; AAI06075.1; -; mRNA.
DR PIR; A00578; PHHUPN.
DR RefSeq; NP_000261.2; NM_000270.3.
DR UniGene; Hs.75514; -.
DR PDB; 1M73; X-ray; 2.30 A; E=2-289.
DR PDB; 1PF7; X-ray; 2.60 A; E=1-289.
DR PDB; 1PWY; X-ray; 2.80 A; E=2-289.
DR PDB; 1RCT; X-ray; 2.80 A; E=2-289.
DR PDB; 1RFG; X-ray; 2.90 A; E=2-289.
DR PDB; 1RR6; X-ray; 2.50 A; A=1-289.
DR PDB; 1RSZ; X-ray; 2.20 A; A=1-289.
DR PDB; 1RT9; X-ray; 2.30 A; A=1-289.
DR PDB; 1ULA; X-ray; 2.75 A; A=1-289.
DR PDB; 1ULB; X-ray; 2.75 A; A=1-289.
DR PDB; 1V2H; X-ray; 2.70 A; E=2-289.
DR PDB; 1V3Q; X-ray; 2.80 A; E=2-289.
DR PDB; 1V41; X-ray; 2.85 A; E=2-289.
DR PDB; 1V45; X-ray; 2.86 A; E=2-289.
DR PDB; 1YRY; X-ray; 2.80 A; E=1-289.
DR PDB; 2A0W; X-ray; 2.28 A; A=1-289.
DR PDB; 2A0X; X-ray; 2.28 A; A=1-289.
DR PDB; 2A0Y; X-ray; 2.28 A; A=1-289.
DR PDB; 2OC4; X-ray; 2.59 A; A=1-289.
DR PDB; 2OC9; X-ray; 2.59 A; A=1-289.
DR PDB; 2ON6; X-ray; 2.50 A; A=1-289.
DR PDB; 2Q7O; X-ray; 2.90 A; E=1-289.
DR PDB; 3BGS; X-ray; 2.10 A; A=1-289.
DR PDB; 3D1V; X-ray; 2.70 A; A=1-289.
DR PDB; 3GB9; X-ray; 2.30 A; A/B/C=1-289.
DR PDB; 3GGS; X-ray; 2.52 A; A/B/C=1-289.
DR PDB; 3INY; X-ray; 2.75 A; A=1-289.
DR PDB; 3K8O; X-ray; 2.40 A; E/Q/S/T/U/Y=1-289.
DR PDB; 3K8Q; X-ray; 2.50 A; A=1-289.
DR PDB; 3PHB; X-ray; 2.30 A; E/Q/S/T/U/Y=1-289.
DR PDB; 4EAR; X-ray; 1.70 A; A/B/C=1-289.
DR PDB; 4EB8; X-ray; 2.30 A; A/B/C=1-289.
DR PDB; 4ECE; X-ray; 2.60 A; A/B/C/D/E/F=1-289.
DR PDB; 4GKA; X-ray; 2.20 A; A/B/C/D/E/F=1-289.
DR PDBsum; 1M73; -.
DR PDBsum; 1PF7; -.
DR PDBsum; 1PWY; -.
DR PDBsum; 1RCT; -.
DR PDBsum; 1RFG; -.
DR PDBsum; 1RR6; -.
DR PDBsum; 1RSZ; -.
DR PDBsum; 1RT9; -.
DR PDBsum; 1ULA; -.
DR PDBsum; 1ULB; -.
DR PDBsum; 1V2H; -.
DR PDBsum; 1V3Q; -.
DR PDBsum; 1V41; -.
DR PDBsum; 1V45; -.
DR PDBsum; 1YRY; -.
DR PDBsum; 2A0W; -.
DR PDBsum; 2A0X; -.
DR PDBsum; 2A0Y; -.
DR PDBsum; 2OC4; -.
DR PDBsum; 2OC9; -.
DR PDBsum; 2ON6; -.
DR PDBsum; 2Q7O; -.
DR PDBsum; 3BGS; -.
DR PDBsum; 3D1V; -.
DR PDBsum; 3GB9; -.
DR PDBsum; 3GGS; -.
DR PDBsum; 3INY; -.
DR PDBsum; 3K8O; -.
DR PDBsum; 3K8Q; -.
DR PDBsum; 3PHB; -.
DR PDBsum; 4EAR; -.
DR PDBsum; 4EB8; -.
DR PDBsum; 4ECE; -.
DR PDBsum; 4GKA; -.
DR ProteinModelPortal; P00491; -.
DR SMR; P00491; 2-289.
DR DIP; DIP-50406N; -.
DR IntAct; P00491; 7.
DR MINT; MINT-1375849; -.
DR STRING; 9606.ENSP00000354532; -.
DR BindingDB; P00491; -.
DR ChEMBL; CHEMBL4338; -.
DR DrugBank; DB00787; Aciclovir.
DR DrugBank; DB00242; Cladribine.
DR DrugBank; DB01033; Mercaptopurine.
DR PhosphoSite; P00491; -.
DR DMDM; 108935929; -.
DR OGP; P00491; -.
DR PaxDb; P00491; -.
DR PRIDE; P00491; -.
DR Ensembl; ENST00000361505; ENSP00000354532; ENSG00000198805.
DR GeneID; 4860; -.
DR KEGG; hsa:4860; -.
DR UCSC; uc001vxo.4; human.
DR CTD; 4860; -.
DR GeneCards; GC14P021021; -.
DR HGNC; HGNC:7892; PNP.
DR HPA; HPA001625; -.
DR MIM; 164050; gene.
DR MIM; 613179; phenotype.
DR neXtProt; NX_P00491; -.
DR Orphanet; 760; Purine nucleoside phosphorylase deficiency.
DR PharmGKB; PA31694; -.
DR eggNOG; COG0005; -.
DR HOVERGEN; HBG002460; -.
DR KO; K03783; -.
DR OMA; ITDHINY; -.
DR PhylomeDB; P00491; -.
DR BioCyc; MetaCyc:HS02151-MONOMER; -.
DR BRENDA; 2.4.2.1; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P00491; -.
DR SignaLink; P00491; -.
DR UniPathway; UPA00606; -.
DR ChiTaRS; PNP; human.
DR EvolutionaryTrace; P00491; -.
DR GeneWiki; Purine_nucleoside_phosphorylase; -.
DR GenomeRNAi; 4860; -.
DR NextBio; 18722; -.
DR PRO; PR:P00491; -.
DR ArrayExpress; P00491; -.
DR Bgee; P00491; -.
DR CleanEx; HS_NP; -.
DR Genevestigator; P00491; -.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0008144; F:drug binding; IDA:UniProtKB.
DR GO; GO:0001882; F:nucleoside binding; IDA:UniProtKB.
DR GO; GO:0042301; F:phosphate ion binding; IDA:UniProtKB.
DR GO; GO:0002060; F:purine nucleobase binding; IDA:UniProtKB.
DR GO; GO:0004731; F:purine-nucleoside phosphorylase activity; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; IMP:UniProtKB.
DR GO; GO:0006148; P:inosine catabolic process; IDA:MGI.
DR GO; GO:0070970; P:interleukin-2 secretion; IMP:UniProtKB.
DR GO; GO:0034356; P:NAD biosynthesis via nicotinamide riboside salvage pathway; IGI:UniProtKB.
DR GO; GO:0006738; P:nicotinamide riboside catabolic process; IDA:UniProtKB.
DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IDA:MGI.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IDA:MGI.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0006195; P:purine nucleotide catabolic process; TAS:Reactome.
DR GO; GO:0043101; P:purine-containing compound salvage; TAS:Reactome.
DR GO; GO:0042493; P:response to drug; IDA:UniProtKB.
DR GO; GO:0034418; P:urate biosynthetic process; IDA:MGI.
DR Gene3D; 3.40.50.1580; -; 1.
DR InterPro; IPR000845; Nucleoside_phosphorylase_d.
DR InterPro; IPR001369; PNP/MTAP.
DR InterPro; IPR011270; Pur_Nuc_Pase_Ino/Guo-sp.
DR InterPro; IPR011268; Purine_phosphorylase.
DR InterPro; IPR018099; Purine_phosphorylase-2_CS.
DR PANTHER; PTHR11904; PTHR11904; 1.
DR PANTHER; PTHR11904:SF9; PTHR11904:SF9; 1.
DR Pfam; PF01048; PNP_UDP_1; 1.
DR PIRSF; PIRSF000477; PurNPase; 1.
DR TIGRFAMs; TIGR01700; PNPH; 1.
DR TIGRFAMs; TIGR01697; PNPH-PUNA-XAPA; 1.
DR PROSITE; PS01240; PNP_MTAP_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Glycosyltransferase;
KW Polymorphism; Reference proteome; Transferase.
FT CHAIN 1 289 Purine nucleoside phosphorylase.
FT /FTId=PRO_0000184536.
FT MOD_RES 1 1 N-acetylmethionine.
FT VARIANT 51 51 G -> S (in dbSNP:rs1049564).
FT /FTId=VAR_002243.
FT VARIANT 89 89 E -> K (in PNPD).
FT /FTId=VAR_002244.
FT VARIANT 128 128 D -> G (in PNPD).
FT /FTId=VAR_002245.
FT VARIANT 174 174 A -> P (in PNPD).
FT /FTId=VAR_002246.
FT VARIANT 192 192 Y -> C (in PNPD).
FT /FTId=VAR_010653.
FT VARIANT 234 234 R -> P (in PNPD).
FT /FTId=VAR_002247.
FT HELIX 7 20
FT STRAND 26 31
FT HELIX 36 41
FT STRAND 43 49
FT HELIX 50 52
FT STRAND 53 55
FT HELIX 62 65
FT STRAND 67 73
FT STRAND 76 83
FT HELIX 87 89
FT HELIX 93 96
FT HELIX 98 106
FT STRAND 110 119
FT STRAND 121 123
FT STRAND 129 137
FT HELIX 138 141
FT TURN 153 155
FT TURN 163 166
FT HELIX 168 179
FT TURN 180 182
FT STRAND 188 194
FT STRAND 197 199
FT HELIX 203 211
FT STRAND 215 221
FT HELIX 222 230
FT STRAND 234 244
FT STRAND 248 250
FT HELIX 257 266
FT HELIX 268 280
FT TURN 285 287
SQ SEQUENCE 289 AA; 32118 MW; 91622FB1D26479D3 CRC64;
MENGYTYEDY KNTAEWLLSH TKHRPQVAII CGSGLGGLTD KLTQAQIFDY GEIPNFPRST
VPGHAGRLVF GFLNGRACVM MQGRFHMYEG YPLWKVTFPV RVFHLLGVDT LVVTNAAGGL
NPKFEVGDIM LIRDHINLPG FSGQNPLRGP NDERFGDRFP AMSDAYDRTM RQRALSTWKQ
MGEQRELQEG TYVMVAGPSF ETVAECRVLQ KLGADAVGMS TVPEVIVARH CGLRVFGFSL
ITNKVIMDYE SLEKANHEEV LAAGKQAAQK LEQFVSILMA SIPLPDKAS
//
MIM
164050
*RECORD*
*FIELD* NO
164050
*FIELD* TI
*164050 PURINE NUCLEOSIDE PHOSPHORYLASE; PNP
;;NUCLEOSIDE PHOSPHORYLASE; NP;;
PURINE-NUCLEOSIDE:ORTHOPHOSPHATE RIBOSYLTRANSFERASE
read more*FIELD* TX
DESCRIPTION
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).
CLONING
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.
MAPPING
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.
MOLECULAR GENETICS
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).
ANIMAL MODEL
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.
*FIELD* AV
.0001
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, GLU89LYS
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.
.0002
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ALA174PRO
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.
.0003
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ASP128GLY
In a patient with nucleoside phosphorylase deficiency (613179), Aust et
al. (1992) found 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.
.0004
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ARG234PRO
See 164050.0003 and Aust et al. (1992). Markert et al. (1997) found the
arg234-to-pro (R234P) mutation in 3 unrelated patients, making this the
most common mutation reported in PNP deficiency to that time.
.0005
NUCLEOSIDE PHOSPHORYLASE POLYMORPHISM
PNP, SER51GLY
See 164050.0003 and Aust et al. (1992).
.0006
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, TYR192CYS
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.
.0007
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
NP, 1-BP DEL
See 164050.0006 and Pannicke et al. (1996).
.0008
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ARG24TER
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.
.0009
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ARG58TER
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.
.0010
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, IVS3DS, G-A, +1
See 164050.0009 and Dalal et al. (2001).
*FIELD* SA
Aitken and Ferguson-Smith (1978); Denny et al. (1978); Junien et al.
(1980)
*FIELD* RF
1. Aitken, D. A.; Ferguson-Smith, M. A.: Regional assignment of nucleoside
phosphorylase by exclusion to 14q13. Cytogenet. Cell Genet. 22:
490-492, 1978.
2. 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.
3. 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.
4. 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.
5. Denny, R. M.; Borgaonkar, D.; Ruddle, F. H.: Order of genes for
NP and TRPRS on chromosome 14. Cytogenet. Cell Genet. 22: 493-497,
1978.
6. Edwards, Y. H.; Hopkinson, D. A.; Harris, H.: Inherited variants
of human nucleoside phosphorylase. Ann. Hum. Genet. 34: 395-408,
1971.
7. 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.
8. Frecker, M.; Dallaire, L.; Young, S. R.; Chen, G. C. C.; Simpson,
N. E.: Confirmation of regional assignment of nucleoside phosphorylase
(NP) on chromosome 14 by gene dosage studies. Hum. Genet. 45: 167-173,
1978.
9. George, D. L.; Francke, U.: Gene dose effect: regional mapping
of human nucleoside phosphorylase on chromosome 14. Science 194:
851-852, 1976.
10. 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.
11. Junien, C.; Kaplan, J. C.; Raoul, O.; Rethore, M.-O.; Turleau,
C.; de Grouchy, J.: Effet de dosage sesquialtere de la nucleoside
phosphorylase erythrocytaire et leucocytaire dans deux cas de trisomie
partielle 14q. Ann. Genet. 23: 86-88, 1980.
12. Markert, M. L.: Personal Communication. Durham, N. C. 10/22/1992.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Williams, S. R.; Goddard, J. M.; Martin, D. W., Jr.: Human purine
nucleoside phosphorylase cDNA sequence and genomic clone characterization. Nucleic
Acids Res. 12: 5779-5787, 1984.
22. 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.
*FIELD* CN
Victor A. McKusick - updated: 9/4/2001
Victor A. McKusick - updated: 8/19/1998
Victor A. McKusick - updated: 5/5/1997
Victor A. McKusick - updated: 4/21/1997
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 10/04/2013
carol: 12/16/2009
ckniffin: 12/16/2009
carol: 12/14/2009
terry: 2/2/2009
ckniffin: 10/28/2004
joanna: 3/17/2004
alopez: 9/7/2001
terry: 9/4/2001
carol: 11/13/2000
carol: 8/24/1998
terry: 8/19/1998
mark: 5/5/1997
terry: 4/24/1997
jenny: 4/21/1997
terry: 4/15/1997
jenny: 1/10/1997
terry: 12/26/1996
mimadm: 12/2/1994
warfield: 4/12/1994
carol: 11/3/1992
carol: 10/21/1992
supermim: 3/16/1992
carol: 3/2/1992
*RECORD*
*FIELD* NO
164050
*FIELD* TI
*164050 PURINE NUCLEOSIDE PHOSPHORYLASE; PNP
;;NUCLEOSIDE PHOSPHORYLASE; NP;;
PURINE-NUCLEOSIDE:ORTHOPHOSPHATE RIBOSYLTRANSFERASE
read more*FIELD* TX
DESCRIPTION
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).
CLONING
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.
MAPPING
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.
MOLECULAR GENETICS
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).
ANIMAL MODEL
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.
*FIELD* AV
.0001
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, GLU89LYS
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.
.0002
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ALA174PRO
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.
.0003
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ASP128GLY
In a patient with nucleoside phosphorylase deficiency (613179), Aust et
al. (1992) found 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.
.0004
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ARG234PRO
See 164050.0003 and Aust et al. (1992). Markert et al. (1997) found the
arg234-to-pro (R234P) mutation in 3 unrelated patients, making this the
most common mutation reported in PNP deficiency to that time.
.0005
NUCLEOSIDE PHOSPHORYLASE POLYMORPHISM
PNP, SER51GLY
See 164050.0003 and Aust et al. (1992).
.0006
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, TYR192CYS
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.
.0007
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
NP, 1-BP DEL
See 164050.0006 and Pannicke et al. (1996).
.0008
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ARG24TER
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.
.0009
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, ARG58TER
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.
.0010
NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
PNP, IVS3DS, G-A, +1
See 164050.0009 and Dalal et al. (2001).
*FIELD* SA
Aitken and Ferguson-Smith (1978); Denny et al. (1978); Junien et al.
(1980)
*FIELD* RF
1. Aitken, D. A.; Ferguson-Smith, M. A.: Regional assignment of nucleoside
phosphorylase by exclusion to 14q13. Cytogenet. Cell Genet. 22:
490-492, 1978.
2. 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.
3. 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.
4. 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.
5. Denny, R. M.; Borgaonkar, D.; Ruddle, F. H.: Order of genes for
NP and TRPRS on chromosome 14. Cytogenet. Cell Genet. 22: 493-497,
1978.
6. Edwards, Y. H.; Hopkinson, D. A.; Harris, H.: Inherited variants
of human nucleoside phosphorylase. Ann. Hum. Genet. 34: 395-408,
1971.
7. 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.
8. Frecker, M.; Dallaire, L.; Young, S. R.; Chen, G. C. C.; Simpson,
N. E.: Confirmation of regional assignment of nucleoside phosphorylase
(NP) on chromosome 14 by gene dosage studies. Hum. Genet. 45: 167-173,
1978.
9. George, D. L.; Francke, U.: Gene dose effect: regional mapping
of human nucleoside phosphorylase on chromosome 14. Science 194:
851-852, 1976.
10. 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.
11. Junien, C.; Kaplan, J. C.; Raoul, O.; Rethore, M.-O.; Turleau,
C.; de Grouchy, J.: Effet de dosage sesquialtere de la nucleoside
phosphorylase erythrocytaire et leucocytaire dans deux cas de trisomie
partielle 14q. Ann. Genet. 23: 86-88, 1980.
12. Markert, M. L.: Personal Communication. Durham, N. C. 10/22/1992.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Williams, S. R.; Goddard, J. M.; Martin, D. W., Jr.: Human purine
nucleoside phosphorylase cDNA sequence and genomic clone characterization. Nucleic
Acids Res. 12: 5779-5787, 1984.
22. 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.
*FIELD* CN
Victor A. McKusick - updated: 9/4/2001
Victor A. McKusick - updated: 8/19/1998
Victor A. McKusick - updated: 5/5/1997
Victor A. McKusick - updated: 4/21/1997
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 10/04/2013
carol: 12/16/2009
ckniffin: 12/16/2009
carol: 12/14/2009
terry: 2/2/2009
ckniffin: 10/28/2004
joanna: 3/17/2004
alopez: 9/7/2001
terry: 9/4/2001
carol: 11/13/2000
carol: 8/24/1998
terry: 8/19/1998
mark: 5/5/1997
terry: 4/24/1997
jenny: 4/21/1997
terry: 4/15/1997
jenny: 1/10/1997
terry: 12/26/1996
mimadm: 12/2/1994
warfield: 4/12/1994
carol: 11/3/1992
carol: 10/21/1992
supermim: 3/16/1992
carol: 3/2/1992
MIM
613179
*RECORD*
*FIELD* NO
613179
*FIELD* TI
#613179 PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
;;NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because purine nucleoside
phosphorylase deficiency is caused by mutation in the PNP gene (164050).
DESCRIPTION
Purine nucleoside phosphorylase deficiency is a rare autosomal recessive
immunodeficiency disorder characterized mainly by decreased T-cell
function. Some patients also have neurologic impairment (review by Aust
et al., 1992).
CLINICAL FEATURES
Hagberg et al. (1970) described brother and sister with ataxic diplegia
and defective cellular immunity. At age 15 months, the sister had
vaccinia gangrenosa, which was successfully drug-treated. She died of
generalized varicella at age 4.5 years. The brother died at age 5 years
of brain abscess.
Giblett et al. (1975) reported a child with severely defective T-cell
immunity and normal B-cell immunity associated with absence of red cell
nucleoside phosphorylase. The parents were consanguineous, and each
showed less than half the normal activity of the enzyme in their red
cells (Berglund et al., 1975). Deficiency of adenosine deaminase
(608958), the next enzyme in the pathway, results in severe combined
immune deficiency (SCID; 102700).
Cohen et al. (1976) reported a girl with purine nucleoside phosphorylase
deficiency and immune defect who had severe hypouricemia and
hypouricosuria, but excessive amounts of purines (mainly inosine and
guanosine) in the urine. Patient erythrocytes, but not cultured
fibroblasts, contained increased concentrations of
phosphoribosylpyrophosphate and inosine. The metabolic abnormalities
resembled those in the erythrocytes of patients with the Lesch-Nyhan
syndrome (300322). The immune defect was thought to be related to
inhibition of adenosine deaminase by inosine.
Stoop et al. (1977) studied a 15-month-old girl, 2 sisters of whom had
died of immunodeficiency. PNP was lacking from red cells and
lymphocytes. The parents and a normal brother had intermediate levels.
Both T cells and B cells were normal at birth, but thereafter a gradual
decrease in T-cell immunity occurred. The patient showed high inosine
and guanosine levels in the blood, as well as hypouricemia and
hypouricosuria. She also had spastic tetraparesis.
In a patient with severely defective T-cell function and normal B-cell
function, Osborne et al. (1977) found no detectable red cell PNP and no
detectable immunologically reactive material. The parents, second
cousins, had less than half the normal enzyme activity. Two patients in
a second family had 0.5% residual enzyme activity and about half-normal
immunologically reactive material. The parents, who were not related,
showed electrophoretically different mutant enzymes that were also
different from those in the first family. The findings indicated that
the affected children in the second family were genetic compounds, not
true homozygotes.
The immune defect from PNP deficiency is often accompanied by a
neurologic disorder. Watson et al. (1981) reported a 2.5-year-old boy
with the disorder who died of malignant lymphoma of the B-immunoblastic
type, who also had spastic tetraplegia.
Rijksen et al. (1987) described a case in a 3-year-old boy who was
admitted for investigation of a behavioral disorder and spastic
diplegia. Severe lymphopenia was found; however, clinical symptoms of
immune deficiency did not become apparent until the age of 4 years.
Stephenson and Tolmie (1990) stated that the family reported by
Graham-Pole et al. (1975) as having 'familial dysequilibrium-diplegia
with T-lymphocyte deficiency' turned out to have PNP deficiency. The
condition was diagnosed retrospectively from stored fibroblasts from an
affected child and from demonstration that both parents had half-normal
activity of PNP. Stephenson and Tolmie (1990) were prompted to restudy
this family after diagnosing PNP deficiency in a young girl who
presented with dysequilibrium syndrome with pyramidal signs, including
extensor plantar responses and exaggerated reflexes but not prominent
spasticity, very similar to the neurologic picture in the family
reported by Graham-Pole et al. (1975). The child had defective
cell-mediated immunity and died of lymphoma shortly after her third
birthday.
Dalal et al. (2001) reported a 4.5-year-old boy, born of a Caucasian
father and Japanese mother, who had immunodeficiency associated with a
mild delay in gross motor development. Although he did not have severe
infections in infancy, he experienced an uneventful varicella infection
at age 8 months, and was referred at age 26 months after a prolonged
parvovirus infection that induced pure red cell aplasia. Physical
examination showed mild ataxia and delayed speech and motor development.
Laboratory studies showed normal immunoglobulins, but decreased number
of T cells and reduced mitogenic responses. PNP enzyme activity was
essentially undetectable; PNP activity in the parents and 2 healthy
sisters was about half of control values.
PATHOGENESIS
Mitchell et al. (1978) found that deoxyadenosine and deoxyguanosine are
particularly toxic to T cells but not to B cells. Addition of
deoxycytidine or dipyridamole prevented deoxyribonucleoside toxicity.
In T cells, the absence of PNP activity is thought to lead to an
accumulation of deoxyguanosine triphosphate, which inhibits the enzyme
ribonucleotide reductase (Mitchell et al., 1978; Ullman et al., 1979).
This inhibition blocks DNA synthesis, thereby preventing the cellular
proliferation required for an immune response.
Although early studies suggested that B-cell function is normal or even
increased in PNP deficiency, later studies showed that B-cell function
can be disrupted as well (Markert, 1991). This was the case in a patient
in whom the nature of the molecular defects was demonstrated by Aust et
al. (1992): she had normal B-cell counts but significantly depressed
immunoglobulin levels.
MOLECULAR GENETICS
In a patient with nucleoside phosphorylase deficiency, 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).
ANIMAL MODEL
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.
*FIELD* SA
Carapella De Luca et al. (1986); Cohen et al. (1977); Fox and Andres
(1977); Gelfand et al. (1978); Junien et al. (1980); Markert and Barrett
(1989); Markert et al. (1997); Osborne and Scott (1980); Pannicke
et al. (1996); Rich et al. (1980); Sasaki et al. (1998); Wortmann
et al. (1979)
*FIELD* RF
1. 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.
2. Berglund, C.; Ammann, A. J.; Giblett, E. R.: Characteristics of
nucleoside phosphorylase in the parents of a child with deficiency
of the enzyme. (Abstract) Am. J. Hum. Genet. 27: 17A only, 1975.
3. Carapella De Luca, E.; Stegagno, M.; Dionisi Vici, C.; Paesano,
R.; Fairbanks, L. D.; Morris, G. S.; Simmonds, H. A.: Prenatal exclusion
of purine nucleoside phosphorylase deficiency. Europ. J. Pediat. 145:
51-53, 1986.
4. Cohen, A.; Doyle, D.; Martin, D. W., Jr.; Ammann, A. J.: Abnormal
purine metabolism and purine overproduction in a patient deficient
in purine nucleoside phosphorylase. New Eng. J. Med. 295: 1449-1454,
1976.
5. Cohen, A.; Staal, G. E. J.; Ammann, A. J.; Martin, D. W., Jr.:
Orotic aciduria in two unrelated patients with inherited deficiencies
of purine nucleoside phosphorylase. J. Clin. Invest. 60: 491-494,
1977.
6. 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.
7. Fox, I. H.; Andres, C. M.: Purine nucleoside phosphorylase deficiency:
altered kinetic properties of a mutant enzyme. Science 197: 1084-1086,
1977.
8. Gelfand, E. W.; Dosch, H.-M.; Biggar, W. D.; Fox, I. H.: Partial
purine nucleoside phosphorylase deficiency: studies of lymphocyte
function. J. Clin. Invest. 61: 1071-1080, 1978.
9. Giblett, E. R.; Ammann, A. J.; Wara, D. W.; Sandman, R. D.; Diamond,
L. K.: Nucleoside-phosphorylase deficiency in a child with severely
defective T-cell immunity and normal B-cell immunity. Lancet 305:
1010-1013, 1975. Note: Originally Volume I.
10. Graham-Pole, J.; Ferguson, A.; Gibson, A. A. M.; Stephenson, J.
B. P.: Familial dysequilibrium-diplegia with T-lymphocyte deficiency. Arch.
Dis. Child. 50: 927-933, 1975.
11. Hagberg, B.; Hansson, O.; Liden, S.; Nilsson, K.: Familial ataxic
diplegia with deficient cellular immunity. A new clinical entity. Acta
Paediat. Scand. 59: 545-550, 1970.
12. Junien, C.; Kaplan, J. C.; Raoul, O.; Rethore, M.-O.; Turleau,
C.; de Grouchy, J.: Effet de dosage sesquialtere de la nucleoside
phosphorylase erythrocytaire et leucocytaire dans deux cas de trisomie
partielle 14q. Ann. Genet. 23: 86-88, 1980.
13. Markert, M. L.: Purine nucleoside phosphorylase deficiency. Immunodef.
Rev. 3: 45-81, 1991.
14. 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.
15. 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.
16. Mitchell, B. S.; Mejias, E.; Daddona, P. E.; Kelley, W. N.: Purinogenic
immunodeficiency diseases: selective toxicity of deoxyribonucleosides
for T-cells. Proc. Nat. Acad. Sci. 75: 5011-5014, 1978.
17. Osborne, W. R. A.; Chen, S.-H.; Giblett, E. R.; Biggar, W. D.;
Ammann, A. A.; Scott, C. R.: Purine nucleoside phosphorylase deficiency:
evidence for molecular heterogeneity in two families with enzyme-deficient
members. J. Clin. Invest. 60: 741-746, 1977.
18. Osborne, W. R. A.; Scott, C. R.: Purine nucleoside phosphorylase
deficiency: measurement of variant protein in four families with enzyme-deficient
members by an enzyme-linked immunosorbent assay. Am. J. Hum. Genet. 32:
927-933, 1980.
19. 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.
20. Rich, K. C.; Mejias, E.; Fox, I. H.: Purine nucleoside phosphorylase
deficiency: improved metabolic and immunologic function with erythrocyte
transfusions. New Eng. J. Med. 303: 973-977, 1980.
21. Rijksen, G.; Kuis, W.; Wadman, S. K.; Spaapen, L. J. M.; Duran,
M.; Voorbrood, B. S.; Staal, G. E. J.; Stoop, J. W.; Zegers, B. J.
M.: A new case of purine nucleoside phosphorylase deficiency: enzymologic,
clinical, and immunologic characteristics. Pediat. Res. 21: 137-141,
1987.
22. 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.
23. 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.
24. Stephenson, J. B. P.; Tolmie, J. L.: Personal Communication. Glasgow,
Scotland 9/27/1990.
25. Stoop, J. W.; Zegers, B. J. M.; Hendricks, G. F. M.; Van Heukelom,
L. H. S.; Staal, G. E. J.; DeBree, P. K.; Wadman, S. K.; Ballieux,
R. E.: Purine nucleoside phosphorylase deficiency associated with
selective cellular immunodeficiency. New Eng. J. Med. 296: 651-655,
1977.
26. Ullman, B.; Gudas, L. J.; Clift, S. M.; Martin, D. W., Jr.: Isolation
and characterization of purine-nucleoside phosphorylase-deficient
T-lymphoma cells and secondary mutants with altered ribonucleotide
reductase: genetic model for immunodeficiency disease. Proc. Nat.
Acad. Sci. 76: 1074-1078, 1979.
27. Watson, A. R.; Evans, D. I. K.; Marsden, H. B.; Miller, V.; Rogers,
P. A.: Purine nucleoside phosphorylase deficiency associated with
a fatal lymphoproliferative disorder. Arch. Dis. Child. 56: 563-565,
1981.
28. 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.
29. Wortmann, R. L.; Andres, C.; Kaminska, J.; Mejias, E.; Gelfand,
E.; Arnold, W.; Rich, K.; Fox, I. H.: Purine nucleoside phosphorylase
deficiency: biochemical properties and heterogeneity in two families. Arthritis
Rheum. 22: 524-531, 1979.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Sinusitis;
[Ears];
Otitis media
CARDIOVASCULAR:
[Vascular];
Cerebral vasculitis
RESPIRATORY:
[Nasopharynx];
Atrophic tonsils;
[Airways];
Upper respiratory tract infections;
Lower respiratory tract infections;
[Lung];
Pneumonia
ABDOMEN:
[Spleen];
Splenomegaly
GENITOURINARY:
[Kidneys];
Urinary tract infections
NEUROLOGIC:
[Central nervous system];
Spastic diplegia;
Tetraparesis;
Ataxia;
Tremor;
Retarded motor development;
Hypertonia;
Hypotonia;
Behavioral problems;
Varying degree of mental retardation;
Cerebral vasculitis
HEMATOLOGY:
Autoimmune hemolytic anemia;
Idiopathic thrombocytopenia;
Autoimmune neutropenia
IMMUNOLOGY:
Frequent bacterial, viral, and opportunistic infections;
Lymphopenia;
Small lymph nodes, which lack paracortical regions;
Small or absent thymus, which contains poorly formed Hassal corpuscles;
Marked depletion of lymphoid tissues;
Markedly depressed T lymphocyte proportion;
Markedly reduced T cell function;
Abnormal B cell function;
Defective antibody production
NEOPLASIA:
Lymphoma;
Lymphosarcoma
LABORATORY ABNORMALITIES:
Reduced erythrocyte purine nucleoside phosphorylase activity;
Low serum uric acid;
Low urine uric acid;
High serum inosine levels;
High serum guanosine levels;
High urinary excretion of inosine, 2'deoxyinosine, guanosine, and
2'deoxyguanosine
MOLECULAR BASIS:
Caused by mutation in the purine nucleoside phosphorylase gene (PNP,
164050.0001)
*FIELD* CN
Ada Hamosh - reviewed: 1/4/2001
Assil Saleh - revised: 8/25/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 03/24/2010
ckniffin: 12/21/2009
joanna: 10/3/2005
joanna: 1/5/2001
joanna: 1/4/2001
kayiaros: 8/25/2000
*FIELD* CN
Victor A. McKusick - updated: 9/4/2001
Victor A. McKusick - updated: 8/19/1998
Victor A. McKusick - updated: 5/5/1997
Victor A. McKusick - updated: 4/21/1997
*FIELD* CD
Cassandra L. Kniffin: 12/15/2009
*FIELD* ED
carol: 01/08/2013
carol: 3/22/2010
ckniffin: 12/17/2009
carol: 12/16/2009
ckniffin: 12/16/2009
*RECORD*
*FIELD* NO
613179
*FIELD* TI
#613179 PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
;;NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because purine nucleoside
phosphorylase deficiency is caused by mutation in the PNP gene (164050).
DESCRIPTION
Purine nucleoside phosphorylase deficiency is a rare autosomal recessive
immunodeficiency disorder characterized mainly by decreased T-cell
function. Some patients also have neurologic impairment (review by Aust
et al., 1992).
CLINICAL FEATURES
Hagberg et al. (1970) described brother and sister with ataxic diplegia
and defective cellular immunity. At age 15 months, the sister had
vaccinia gangrenosa, which was successfully drug-treated. She died of
generalized varicella at age 4.5 years. The brother died at age 5 years
of brain abscess.
Giblett et al. (1975) reported a child with severely defective T-cell
immunity and normal B-cell immunity associated with absence of red cell
nucleoside phosphorylase. The parents were consanguineous, and each
showed less than half the normal activity of the enzyme in their red
cells (Berglund et al., 1975). Deficiency of adenosine deaminase
(608958), the next enzyme in the pathway, results in severe combined
immune deficiency (SCID; 102700).
Cohen et al. (1976) reported a girl with purine nucleoside phosphorylase
deficiency and immune defect who had severe hypouricemia and
hypouricosuria, but excessive amounts of purines (mainly inosine and
guanosine) in the urine. Patient erythrocytes, but not cultured
fibroblasts, contained increased concentrations of
phosphoribosylpyrophosphate and inosine. The metabolic abnormalities
resembled those in the erythrocytes of patients with the Lesch-Nyhan
syndrome (300322). The immune defect was thought to be related to
inhibition of adenosine deaminase by inosine.
Stoop et al. (1977) studied a 15-month-old girl, 2 sisters of whom had
died of immunodeficiency. PNP was lacking from red cells and
lymphocytes. The parents and a normal brother had intermediate levels.
Both T cells and B cells were normal at birth, but thereafter a gradual
decrease in T-cell immunity occurred. The patient showed high inosine
and guanosine levels in the blood, as well as hypouricemia and
hypouricosuria. She also had spastic tetraparesis.
In a patient with severely defective T-cell function and normal B-cell
function, Osborne et al. (1977) found no detectable red cell PNP and no
detectable immunologically reactive material. The parents, second
cousins, had less than half the normal enzyme activity. Two patients in
a second family had 0.5% residual enzyme activity and about half-normal
immunologically reactive material. The parents, who were not related,
showed electrophoretically different mutant enzymes that were also
different from those in the first family. The findings indicated that
the affected children in the second family were genetic compounds, not
true homozygotes.
The immune defect from PNP deficiency is often accompanied by a
neurologic disorder. Watson et al. (1981) reported a 2.5-year-old boy
with the disorder who died of malignant lymphoma of the B-immunoblastic
type, who also had spastic tetraplegia.
Rijksen et al. (1987) described a case in a 3-year-old boy who was
admitted for investigation of a behavioral disorder and spastic
diplegia. Severe lymphopenia was found; however, clinical symptoms of
immune deficiency did not become apparent until the age of 4 years.
Stephenson and Tolmie (1990) stated that the family reported by
Graham-Pole et al. (1975) as having 'familial dysequilibrium-diplegia
with T-lymphocyte deficiency' turned out to have PNP deficiency. The
condition was diagnosed retrospectively from stored fibroblasts from an
affected child and from demonstration that both parents had half-normal
activity of PNP. Stephenson and Tolmie (1990) were prompted to restudy
this family after diagnosing PNP deficiency in a young girl who
presented with dysequilibrium syndrome with pyramidal signs, including
extensor plantar responses and exaggerated reflexes but not prominent
spasticity, very similar to the neurologic picture in the family
reported by Graham-Pole et al. (1975). The child had defective
cell-mediated immunity and died of lymphoma shortly after her third
birthday.
Dalal et al. (2001) reported a 4.5-year-old boy, born of a Caucasian
father and Japanese mother, who had immunodeficiency associated with a
mild delay in gross motor development. Although he did not have severe
infections in infancy, he experienced an uneventful varicella infection
at age 8 months, and was referred at age 26 months after a prolonged
parvovirus infection that induced pure red cell aplasia. Physical
examination showed mild ataxia and delayed speech and motor development.
Laboratory studies showed normal immunoglobulins, but decreased number
of T cells and reduced mitogenic responses. PNP enzyme activity was
essentially undetectable; PNP activity in the parents and 2 healthy
sisters was about half of control values.
PATHOGENESIS
Mitchell et al. (1978) found that deoxyadenosine and deoxyguanosine are
particularly toxic to T cells but not to B cells. Addition of
deoxycytidine or dipyridamole prevented deoxyribonucleoside toxicity.
In T cells, the absence of PNP activity is thought to lead to an
accumulation of deoxyguanosine triphosphate, which inhibits the enzyme
ribonucleotide reductase (Mitchell et al., 1978; Ullman et al., 1979).
This inhibition blocks DNA synthesis, thereby preventing the cellular
proliferation required for an immune response.
Although early studies suggested that B-cell function is normal or even
increased in PNP deficiency, later studies showed that B-cell function
can be disrupted as well (Markert, 1991). This was the case in a patient
in whom the nature of the molecular defects was demonstrated by Aust et
al. (1992): she had normal B-cell counts but significantly depressed
immunoglobulin levels.
MOLECULAR GENETICS
In a patient with nucleoside phosphorylase deficiency, 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).
ANIMAL MODEL
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.
*FIELD* SA
Carapella De Luca et al. (1986); Cohen et al. (1977); Fox and Andres
(1977); Gelfand et al. (1978); Junien et al. (1980); Markert and Barrett
(1989); Markert et al. (1997); Osborne and Scott (1980); Pannicke
et al. (1996); Rich et al. (1980); Sasaki et al. (1998); Wortmann
et al. (1979)
*FIELD* RF
1. 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.
2. Berglund, C.; Ammann, A. J.; Giblett, E. R.: Characteristics of
nucleoside phosphorylase in the parents of a child with deficiency
of the enzyme. (Abstract) Am. J. Hum. Genet. 27: 17A only, 1975.
3. Carapella De Luca, E.; Stegagno, M.; Dionisi Vici, C.; Paesano,
R.; Fairbanks, L. D.; Morris, G. S.; Simmonds, H. A.: Prenatal exclusion
of purine nucleoside phosphorylase deficiency. Europ. J. Pediat. 145:
51-53, 1986.
4. Cohen, A.; Doyle, D.; Martin, D. W., Jr.; Ammann, A. J.: Abnormal
purine metabolism and purine overproduction in a patient deficient
in purine nucleoside phosphorylase. New Eng. J. Med. 295: 1449-1454,
1976.
5. Cohen, A.; Staal, G. E. J.; Ammann, A. J.; Martin, D. W., Jr.:
Orotic aciduria in two unrelated patients with inherited deficiencies
of purine nucleoside phosphorylase. J. Clin. Invest. 60: 491-494,
1977.
6. 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.
7. Fox, I. H.; Andres, C. M.: Purine nucleoside phosphorylase deficiency:
altered kinetic properties of a mutant enzyme. Science 197: 1084-1086,
1977.
8. Gelfand, E. W.; Dosch, H.-M.; Biggar, W. D.; Fox, I. H.: Partial
purine nucleoside phosphorylase deficiency: studies of lymphocyte
function. J. Clin. Invest. 61: 1071-1080, 1978.
9. Giblett, E. R.; Ammann, A. J.; Wara, D. W.; Sandman, R. D.; Diamond,
L. K.: Nucleoside-phosphorylase deficiency in a child with severely
defective T-cell immunity and normal B-cell immunity. Lancet 305:
1010-1013, 1975. Note: Originally Volume I.
10. Graham-Pole, J.; Ferguson, A.; Gibson, A. A. M.; Stephenson, J.
B. P.: Familial dysequilibrium-diplegia with T-lymphocyte deficiency. Arch.
Dis. Child. 50: 927-933, 1975.
11. Hagberg, B.; Hansson, O.; Liden, S.; Nilsson, K.: Familial ataxic
diplegia with deficient cellular immunity. A new clinical entity. Acta
Paediat. Scand. 59: 545-550, 1970.
12. Junien, C.; Kaplan, J. C.; Raoul, O.; Rethore, M.-O.; Turleau,
C.; de Grouchy, J.: Effet de dosage sesquialtere de la nucleoside
phosphorylase erythrocytaire et leucocytaire dans deux cas de trisomie
partielle 14q. Ann. Genet. 23: 86-88, 1980.
13. Markert, M. L.: Purine nucleoside phosphorylase deficiency. Immunodef.
Rev. 3: 45-81, 1991.
14. 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.
15. 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.
16. Mitchell, B. S.; Mejias, E.; Daddona, P. E.; Kelley, W. N.: Purinogenic
immunodeficiency diseases: selective toxicity of deoxyribonucleosides
for T-cells. Proc. Nat. Acad. Sci. 75: 5011-5014, 1978.
17. Osborne, W. R. A.; Chen, S.-H.; Giblett, E. R.; Biggar, W. D.;
Ammann, A. A.; Scott, C. R.: Purine nucleoside phosphorylase deficiency:
evidence for molecular heterogeneity in two families with enzyme-deficient
members. J. Clin. Invest. 60: 741-746, 1977.
18. Osborne, W. R. A.; Scott, C. R.: Purine nucleoside phosphorylase
deficiency: measurement of variant protein in four families with enzyme-deficient
members by an enzyme-linked immunosorbent assay. Am. J. Hum. Genet. 32:
927-933, 1980.
19. 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.
20. Rich, K. C.; Mejias, E.; Fox, I. H.: Purine nucleoside phosphorylase
deficiency: improved metabolic and immunologic function with erythrocyte
transfusions. New Eng. J. Med. 303: 973-977, 1980.
21. Rijksen, G.; Kuis, W.; Wadman, S. K.; Spaapen, L. J. M.; Duran,
M.; Voorbrood, B. S.; Staal, G. E. J.; Stoop, J. W.; Zegers, B. J.
M.: A new case of purine nucleoside phosphorylase deficiency: enzymologic,
clinical, and immunologic characteristics. Pediat. Res. 21: 137-141,
1987.
22. 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.
23. 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.
24. Stephenson, J. B. P.; Tolmie, J. L.: Personal Communication. Glasgow,
Scotland 9/27/1990.
25. Stoop, J. W.; Zegers, B. J. M.; Hendricks, G. F. M.; Van Heukelom,
L. H. S.; Staal, G. E. J.; DeBree, P. K.; Wadman, S. K.; Ballieux,
R. E.: Purine nucleoside phosphorylase deficiency associated with
selective cellular immunodeficiency. New Eng. J. Med. 296: 651-655,
1977.
26. Ullman, B.; Gudas, L. J.; Clift, S. M.; Martin, D. W., Jr.: Isolation
and characterization of purine-nucleoside phosphorylase-deficient
T-lymphoma cells and secondary mutants with altered ribonucleotide
reductase: genetic model for immunodeficiency disease. Proc. Nat.
Acad. Sci. 76: 1074-1078, 1979.
27. Watson, A. R.; Evans, D. I. K.; Marsden, H. B.; Miller, V.; Rogers,
P. A.: Purine nucleoside phosphorylase deficiency associated with
a fatal lymphoproliferative disorder. Arch. Dis. Child. 56: 563-565,
1981.
28. 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.
29. Wortmann, R. L.; Andres, C.; Kaminska, J.; Mejias, E.; Gelfand,
E.; Arnold, W.; Rich, K.; Fox, I. H.: Purine nucleoside phosphorylase
deficiency: biochemical properties and heterogeneity in two families. Arthritis
Rheum. 22: 524-531, 1979.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Sinusitis;
[Ears];
Otitis media
CARDIOVASCULAR:
[Vascular];
Cerebral vasculitis
RESPIRATORY:
[Nasopharynx];
Atrophic tonsils;
[Airways];
Upper respiratory tract infections;
Lower respiratory tract infections;
[Lung];
Pneumonia
ABDOMEN:
[Spleen];
Splenomegaly
GENITOURINARY:
[Kidneys];
Urinary tract infections
NEUROLOGIC:
[Central nervous system];
Spastic diplegia;
Tetraparesis;
Ataxia;
Tremor;
Retarded motor development;
Hypertonia;
Hypotonia;
Behavioral problems;
Varying degree of mental retardation;
Cerebral vasculitis
HEMATOLOGY:
Autoimmune hemolytic anemia;
Idiopathic thrombocytopenia;
Autoimmune neutropenia
IMMUNOLOGY:
Frequent bacterial, viral, and opportunistic infections;
Lymphopenia;
Small lymph nodes, which lack paracortical regions;
Small or absent thymus, which contains poorly formed Hassal corpuscles;
Marked depletion of lymphoid tissues;
Markedly depressed T lymphocyte proportion;
Markedly reduced T cell function;
Abnormal B cell function;
Defective antibody production
NEOPLASIA:
Lymphoma;
Lymphosarcoma
LABORATORY ABNORMALITIES:
Reduced erythrocyte purine nucleoside phosphorylase activity;
Low serum uric acid;
Low urine uric acid;
High serum inosine levels;
High serum guanosine levels;
High urinary excretion of inosine, 2'deoxyinosine, guanosine, and
2'deoxyguanosine
MOLECULAR BASIS:
Caused by mutation in the purine nucleoside phosphorylase gene (PNP,
164050.0001)
*FIELD* CN
Ada Hamosh - reviewed: 1/4/2001
Assil Saleh - revised: 8/25/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 03/24/2010
ckniffin: 12/21/2009
joanna: 10/3/2005
joanna: 1/5/2001
joanna: 1/4/2001
kayiaros: 8/25/2000
*FIELD* CN
Victor A. McKusick - updated: 9/4/2001
Victor A. McKusick - updated: 8/19/1998
Victor A. McKusick - updated: 5/5/1997
Victor A. McKusick - updated: 4/21/1997
*FIELD* CD
Cassandra L. Kniffin: 12/15/2009
*FIELD* ED
carol: 01/08/2013
carol: 3/22/2010
ckniffin: 12/17/2009
carol: 12/16/2009
ckniffin: 12/16/2009