RBCC Red Blood Cell Collection

PON1 (PON) [Confidence: low (only semi-automatic identification from reviews)]
Serum paraoxonase/arylesterase 1; PON 1; 3.1.1.2; 3.1.1.81; 3.1.8.1 (Aromatic esterase 1; A-esterase 1; K-45; Serum aryldialkylphosphatase 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P27169
ID PON1_HUMAN Reviewed; 355 AA.
AC P27169; B2RA40; Q16052; Q6B0J6; Q9UCB1;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 3.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Serum paraoxonase/arylesterase 1;
DE Short=PON 1;
DE EC=3.1.1.2;
DE EC=3.1.1.81;
DE EC=3.1.8.1;
DE AltName: Full=Aromatic esterase 1;
DE Short=A-esterase 1;
DE AltName: Full=K-45;
DE AltName: Full=Serum aryldialkylphosphatase 1;
GN Name=PON1; Synonyms=PON;
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 VARIANTS MET-55 AND ARG-192.
RC TISSUE=Liver;
RX PubMed=1657140; DOI=10.1021/bi00106a010;
RA Hassett C., Richter R.J., Humbert R., Chapline C., Crabb J.W.,
RA Omiecinski C.J., Furlong C.E.;
RT "Characterization of cDNA clones encoding rabbit and human serum
RT paraoxonase: the mature protein retains its signal sequence.";
RL Biochemistry 30:10141-10149(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS MET-55 AND ARG-192.
RX PubMed=7916578;
RA Adkins S., Gan K.N., Mody M., La Du B.N.;
RT "Molecular basis for the polymorphic forms of human serum
RT paraoxonase/arylesterase: glutamine or arginine at position 191, for
RT the respective A or B allozymes.";
RL Am. J. Hum. Genet. 52:598-608(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND VARIANTS MET-55
RP AND ARG-192.
RC TISSUE=Liver;
RX PubMed=8393742; DOI=10.1016/0009-2797(93)90022-Q;
RA La Du B.N., Adkins S., Kuo C.L., Lipsig D.;
RT "Studies on human serum paraoxonase/arylesterase.";
RL Chem. Biol. Interact. 87:25-34(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MET-55 AND ARG-192, AND
RP CHARACTERIZATION.
RC TISSUE=Liver;
RX PubMed=8393745; DOI=10.1016/0009-2797(93)90023-R;
RA Furlong C.E., Costa L.G., Hassett C., Richter R.J., Sundstrom J.A.,
RA Adler D.A., Disteche C.M., Omiecinski C.J., Chapline C., Crabb J.W.;
RT "Human and rabbit paraoxonases: purification, cloning, sequencing,
RT mapping and role of polymorphism in organophosphate detoxification.";
RL Chem. Biol. Interact. 87:35-48(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MET-55.
RC TISSUE=Lymphoblast;
RX PubMed=8812495; DOI=10.1006/geno.1996.0401;
RA Clendenning J.B., Humbert R., Green E.D., Wood C., Traver D.,
RA Furlong C.E.;
RT "Structural organization of the human PON1 gene.";
RL Genomics 35:586-589(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=9261565;
RA Wang K.K., Wan D.F., Qiu X.K., Lu P.X., Gu J.R.;
RT "Differential expression of a cDNA clone in human liver versus hepatic
RT cancer -- highly homologous to aryl-dialkyl-phosphatase.";
RL Cell Res. 7:79-90(1997).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-55.
RC TISSUE=Liver;
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 [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-192.
RG SeattleSNPs variation discovery resource;
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [11]
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 [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [13]
RP PROTEIN SEQUENCE OF 2-21, AND TISSUE SPECIFICITY.
RX PubMed=8382160; DOI=10.1111/j.1432-1033.1993.tb17620.x;
RA Blatter M.-C., James R.W., Messmer S., Barja F., Pometta D.;
RT "Identification of a distinct human high-density lipoprotein
RT subspecies defined by a lipoprotein-associated protein, K-45. Identity
RT of K-45 with paraoxonase.";
RL Eur. J. Biochem. 211:871-879(1993).
RN [14]
RP PROTEIN SEQUENCE OF 2-21; 234-244; 291-305 AND 350-355, INTERACTION
RP WITH CLU, TISSUE SPECIFICITY, AND DISULFIDE BOND.
RC TISSUE=Plasma;
RX PubMed=8292612; DOI=10.1021/bi00169a026;
RA Kelso G.J., Stuart W.D., Richter R.J., Furlong C.E.,
RA Jordan-Starck T.C., Harmony J.A.K.;
RT "Apolipoprotein J is associated with paraoxonase in human plasma.";
RL Biochemistry 33:832-839(1994).
RN [15]
RP PROTEIN SEQUENCE OF 2-11, AND CATALYTIC ACTIVITY.
RX PubMed=1718413; DOI=10.1021/bi00106a009;
RA Furlong C.E., Richter R.J., Chapline C., Crabb J.W.;
RT "Purification of rabbit and human serum paraoxonase.";
RL Biochemistry 30:10133-10140(1991).
RN [16]
RP CATALYTIC ACTIVITY.
RX PubMed=1673382;
RA Gan K.N., Smolen A., Eckerson H.W., La Du B.N.;
RT "Purification of human serum paraoxonase/arylesterase. Evidence for
RT one esterase catalyzing both activities.";
RL Drug Metab. Dispos. 19:100-106(1991).
RN [17]
RP MUTAGENESIS OF CYS-284.
RX PubMed=7638166; DOI=10.1073/pnas.92.16.7187;
RA Sorenson R.C., Primo-Parmo S.L., Kuo C.-L., Adkins S., Lockridge O.,
RA La Du B.N.;
RT "Reconsideration of the catalytic center and mechanism of mammalian
RT paraoxonase/arylesterase.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7187-7191(1995).
RN [18]
RP MUTAGENESIS OF 20-HIS-GLN-21, AND FUNCTION OF THE UNCLEAVED SIGNAL
RP PEPTIDE.
RX PubMed=10479665;
RA Sorenson R.C., Bisgaier C.L., Aviram M., Hsu C., Billecke S.,
RA La Du B.N.;
RT "Human serum paraoxonase/arylesterase's retained hydrophobic N-
RT terminal leader sequence associates with HDLs by binding
RT phospholipids: apolipoprotein A-I stabilizes activity.";
RL Arterioscler. Thromb. Vasc. Biol. 19:2214-2225(1999).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-253, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=15772423; DOI=10.1194/jlr.M400511-JLR200;
RA Draganov D.I., Teiber J.F., Speelman A., Osawa Y., Sunahara R.,
RA La Du B.N.;
RT "Human paraoxonases (PON1, PON2, and PON3) are lactonases with
RT overlapping and distinct substrate specificities.";
RL J. Lipid Res. 46:1239-1247(2005).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-227; ASN-253 AND ASN-324,
RP AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [22]
RP INTERACTION WITH HPBP.
RX PubMed=16531243; DOI=10.1016/j.str.2005.12.012;
RA Morales R., Berna A., Carpentier P., Contreras-Martel C., Renault F.,
RA Nicodeme M., Chesne-Seck M.-L., Bernier F., Dupuy J., Schaeffer C.,
RA Diemer H., van Dorsselaer A., Fontecilla-Camps J.C., Masson P.,
RA Rochu D., Chabriere E.;
RT "Serendipitous discovery and X-ray structure of a human phosphate
RT binding apolipoprotein.";
RL Structure 14:601-609(2006).
RN [23]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-253 AND ASN-324, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH CALCIUM IONS,
RP MUTAGENESIS OF HIS-115 AND HIS-134, CATALYTIC ACTIVITY, AND DISULFIDE
RP BOND.
RX PubMed=15098021; DOI=10.1038/nsmb767;
RA Harel M., Aharoni A., Gaidukov L., Brumshtein B., Khersonsky O.,
RA Meged R., Dvir H., Ravelli R.B.G., McCarthy A., Toker L., Silman I.,
RA Sussman J.L., Tawfik D.S.;
RT "Structure and evolution of the serum paraoxonase family of
RT detoxifying and anti-atherosclerotic enzymes.";
RL Nat. Struct. Mol. Biol. 11:412-419(2004).
RN [25]
RP VARIANT ARG-192.
RX PubMed=8098250; DOI=10.1038/ng0193-73;
RA Humbert R., Adler D.A., Disteche C.M., Hassett C., Omiecinski C.J.,
RA Furlong C.E.;
RT "The molecular basis of the human serum paraoxonase activity
RT polymorphism.";
RL Nat. Genet. 3:73-76(1993).
RN [26]
RP ASSOCIATION WITH DIABETIC RETINOPATHY SUSCEPTIBILITY.
RX PubMed=9661650; DOI=10.1210/jc.83.7.2589;
RA Kao Y.-L., Donaghue K., Chan A., Knight J., Silink M.;
RT "A variant of paraoxonase (PON1) gene is associated with diabetic
RT retinopathy in IDDM.";
RL J. Clin. Endocrinol. Metab. 83:2589-2592(1998).
RN [27]
RP VARIANT VAL-102.
RX PubMed=12783936; DOI=10.1093/jnci/95.11.812;
RA Marchesani M., Hakkarainen A., Tuomainen T.P., Kaikkonen J.,
RA Pukkala E., Uimari P., Seppala E., Matikainen M., Kallioniemi O.-P.,
RA Schleutker J., Lehtimaki T., Salonen J.T.;
RT "New paraoxonase 1 polymorphism I102V and the risk of prostate cancer
RT in Finnish men.";
RL J. Natl. Cancer Inst. 95:812-818(2003).
RN [28]
RP VARIANT [LARGE SCALE ANALYSIS] ARG-192.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J.,
RA Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C.,
RA Graubert T.A., DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
CC -!- FUNCTION: Hydrolyzes the toxic metabolites of a variety of
CC organophosphorus insecticides. Capable of hydrolyzing a broad
CC spectrum of organophosphate substrates and lactones, and a number
CC of aromatic carboxylic acid esters. Mediates an enzymatic
CC protection of low density lipoproteins against oxidative
CC modification and the consequent series of events leading to
CC atheroma formation.
CC -!- CATALYTIC ACTIVITY: A phenyl acetate + H(2)O = a phenol + acetate.
CC -!- CATALYTIC ACTIVITY: An aryl dialkyl phosphate + H(2)O = dialkyl
CC phosphate + an aryl alcohol.
CC -!- CATALYTIC ACTIVITY: An N-acyl-L-homoserine lactone + H(2)O = an N-
CC acyl-L-homoserine.
CC -!- COFACTOR: Binds 2 calcium ions per subunit.
CC -!- SUBUNIT: Homodimer. Heterooligomer with phosphate-binding protein
CC (HPBP). Interacts with CLU.
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space.
CC -!- TISSUE SPECIFICITY: Plasma, associated with HDL (at protein
CC level). Expressed in liver, but not in heart, brain, placenta,
CC lung, skeletal muscle, kidney or pancreas.
CC -!- PTM: Glycosylated.
CC -!- PTM: The signal sequence is not cleaved.
CC -!- PTM: Present in two forms, form B contains a disulfide bond, form
CC A does not.
CC -!- POLYMORPHISM: The allelic form of the enzyme with Gln-192
CC (allozyme A) hydrolyzes paraoxon with a low turnover number and
CC the one with Arg-192 (allozyme B) with a high turnover number.
CC -!- DISEASE: Microvascular complications of diabetes 5 (MVCD5)
CC [MIM:612633]: Pathological conditions that develop in numerous
CC tissues and organs as a consequence of diabetes mellitus. They
CC include diabetic retinopathy, diabetic nephropathy leading to end-
CC stage renal disease, and diabetic neuropathy. Diabetic retinopathy
CC remains the major cause of new-onset blindness among diabetic
CC adults. It is characterized by vascular permeability and increased
CC tissue ischemia and angiogenesis. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry. Homozygosity for the Leu-55 allele is strongly associated
CC with the development of retinal disease in diabetic patients.
CC -!- MISCELLANEOUS: The preferential association of PON1 with HDL is
CC mediated in part by its signal peptide, by binding phospholipids
CC directly, rather than binding apo AI. The retained signal peptide
CC may allow transfer of the protein between phospholipid surfaces.
CC -!- SIMILARITY: Belongs to the paraoxonase family.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/pon1/";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=PON1";
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DR EMBL; M63012; AAB59538.1; -; mRNA.
DR EMBL; M63013; AAA60142.1; -; mRNA.
DR EMBL; M63014; AAA60143.1; -; mRNA.
DR EMBL; S56555; AAB25717.1; -; Genomic_DNA.
DR EMBL; S56546; AAB25717.1; JOINED; Genomic_DNA.
DR EMBL; S56548; AAB25717.1; JOINED; Genomic_DNA.
DR EMBL; S64696; AAB27899.1; -; mRNA.
DR EMBL; S64615; AAB27714.2; -; mRNA.
DR EMBL; U55885; AAB41835.1; -; Genomic_DNA.
DR EMBL; U55877; AAB41835.1; JOINED; Genomic_DNA.
DR EMBL; U55878; AAB41835.1; JOINED; Genomic_DNA.
DR EMBL; U55879; AAB41835.1; JOINED; Genomic_DNA.
DR EMBL; U55880; AAB41835.1; JOINED; Genomic_DNA.
DR EMBL; U55881; AAB41835.1; JOINED; Genomic_DNA.
DR EMBL; U55882; AAB41835.1; JOINED; Genomic_DNA.
DR EMBL; U55883; AAB41835.1; JOINED; Genomic_DNA.
DR EMBL; D84371; BAA12327.1; -; mRNA.
DR EMBL; U53784; AAA97957.1; -; mRNA.
DR EMBL; Z70723; CAA94728.1; -; mRNA.
DR EMBL; AK314027; BAG36737.1; -; mRNA.
DR EMBL; AF539592; AAM97935.1; -; Genomic_DNA.
DR EMBL; AC004022; AAC35293.1; -; Genomic_DNA.
DR EMBL; CH236949; EAL24133.1; -; Genomic_DNA.
DR EMBL; CH471091; EAW76771.1; -; Genomic_DNA.
DR EMBL; BC074719; AAH74719.1; -; mRNA.
DR PIR; A45451; A45451.
DR RefSeq; NP_000437.3; NM_000446.5.
DR UniGene; Hs.370995; -.
DR PDB; 1V04; X-ray; 2.20 A; A=1-353.
DR PDB; 1XHR; Model; -; A=40-355.
DR PDBsum; 1V04; -.
DR PDBsum; 1XHR; -.
DR ProteinModelPortal; P27169; -.
DR SMR; P27169; 20-355.
DR STRING; 9606.ENSP00000222381; -.
DR BindingDB; P27169; -.
DR ChEMBL; CHEMBL3167; -.
DR DrugBank; DB01076; Atorvastatin.
DR DrugBank; DB01327; Cefazolin.
DR TCDB; 1.A.6.2.6; the epithelial na(+) channel (enac) family.
DR PhosphoSite; P27169; -.
DR DMDM; 308153572; -.
DR SWISS-2DPAGE; P27169; -.
DR PaxDb; P27169; -.
DR PeptideAtlas; P27169; -.
DR PRIDE; P27169; -.
DR Ensembl; ENST00000222381; ENSP00000222381; ENSG00000005421.
DR GeneID; 5444; -.
DR KEGG; hsa:5444; -.
DR UCSC; uc003uns.3; human.
DR CTD; 5444; -.
DR GeneCards; GC07M094926; -.
DR H-InvDB; HIX0033662; -.
DR HGNC; HGNC:9204; PON1.
DR HPA; HPA001610; -.
DR MIM; 168820; gene+phenotype.
DR MIM; 612633; phenotype.
DR neXtProt; NX_P27169; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA33529; -.
DR eggNOG; NOG68009; -.
DR HOGENOM; HOG000252960; -.
DR HOVERGEN; HBG003604; -.
DR InParanoid; P27169; -.
DR KO; K01045; -.
DR PhylomeDB; P27169; -.
DR BRENDA; 3.1.1.2; 2681.
DR SABIO-RK; P27169; -.
DR ChiTaRS; PON1; human.
DR EvolutionaryTrace; P27169; -.
DR GeneWiki; PON1; -.
DR GenomeRNAi; 5444; -.
DR NextBio; 21069; -.
DR PRO; PR:P27169; -.
DR ArrayExpress; P27169; -.
DR Bgee; P27169; -.
DR CleanEx; HS_PON1; -.
DR Genevestigator; P27169; -.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IEA:Ensembl.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0004063; F:aryldialkylphosphatase activity; IDA:UniProtKB.
DR GO; GO:0004064; F:arylesterase activity; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0019439; P:aromatic compound catabolic process; IDA:BHF-UCL.
DR GO; GO:0046395; P:carboxylic acid catabolic process; IDA:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl.
DR GO; GO:0046434; P:organophosphate catabolic process; IDA:BHF-UCL.
DR GO; GO:0046470; P:phosphatidylcholine metabolic process; IDA:BHF-UCL.
DR GO; GO:0051099; P:positive regulation of binding; IDA:BHF-UCL.
DR GO; GO:0010875; P:positive regulation of cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0032411; P:positive regulation of transporter activity; IDA:BHF-UCL.
DR GO; GO:0009605; P:response to external stimulus; NAS:UniProtKB.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR Gene3D; 2.120.10.30; -; 1.
DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like.
DR InterPro; IPR002640; Arylesterase.
DR InterPro; IPR008363; Paraoxonase1.
DR Pfam; PF01731; Arylesterase; 1.
DR PRINTS; PR01785; PARAOXONASE.
DR PRINTS; PR01786; PARAOXONASE1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Complete proteome; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; HDL; Hydrolase; Metal-binding;
KW Polymorphism; Reference proteome; Secreted; Signal.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 355 Serum paraoxonase/arylesterase 1.
FT /FTId=PRO_0000223281.
FT SIGNAL 2 ? Not cleaved.
FT ACT_SITE 115 115 Proton acceptor (Probable).
FT METAL 53 53 Calcium 1; catalytic.
FT METAL 54 54 Calcium 2.
FT METAL 117 117 Calcium 2; via carbonyl oxygen.
FT METAL 168 168 Calcium 1; catalytic.
FT METAL 169 169 Calcium 2.
FT METAL 224 224 Calcium 1; catalytic.
FT METAL 269 269 Calcium 1; catalytic.
FT METAL 270 270 Calcium 1; catalytic.
FT CARBOHYD 227 227 N-linked (GlcNAc...).
FT CARBOHYD 253 253 N-linked (GlcNAc...).
FT CARBOHYD 270 270 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 324 324 N-linked (GlcNAc...).
FT DISULFID 42 353 In form B.
FT VARIANT 55 55 L -> M (in dbSNP:rs854560).
FT /FTId=VAR_006043.
FT VARIANT 102 102 I -> V (polymorphism associated with
FT decreased activity that seems to be
FT associated with an increased risk for
FT prostate cancer).
FT /FTId=VAR_015882.
FT VARIANT 160 160 R -> G (in dbSNP:rs13306698).
FT /FTId=VAR_055342.
FT VARIANT 192 192 Q -> R (polymorphism important for
FT activity; dbSNP:rs662).
FT /FTId=VAR_006044.
FT MUTAGEN 20 21 HQ->AA: The signal peptide is cleaved;
FT not associated with HDL.
FT MUTAGEN 115 115 H->Q: Reduces activity 10000-fold.
FT MUTAGEN 134 134 H->Q: Substantially reduced activity.
FT MUTAGEN 284 284 C->A,S: No loss of activity.
FT HELIX 19 27
FT TURN 28 31
FT STRAND 54 57
FT STRAND 61 67
FT STRAND 84 89
FT STRAND 92 94
FT STRAND 97 99
FT STRAND 101 103
FT STRAND 105 107
FT HELIX 109 111
FT STRAND 114 121
FT STRAND 127 133
FT STRAND 140 147
FT TURN 148 151
FT STRAND 152 159
FT STRAND 165 174
FT STRAND 177 183
FT HELIX 189 197
FT STRAND 203 208
FT STRAND 213 228
FT STRAND 232 239
FT TURN 240 243
FT STRAND 244 250
FT STRAND 256 263
FT STRAND 265 273
FT TURN 275 277
FT STRAND 280 286
FT HELIX 288 292
FT STRAND 302 308
FT STRAND 312 314
FT STRAND 316 323
FT STRAND 325 328
FT STRAND 330 337
FT STRAND 340 348
FT STRAND 350 353
SQ SEQUENCE 355 AA; 39731 MW; 9B5895509166167E CRC64;
MAKLIALTLL GMGLALFRNH QSSYQTRLNA LREVQPVELP NCNLVKGIET GSEDLEILPN
GLAFISSGLK YPGIKSFNPN SPGKILLMDL NEEDPTVLEL GITGSKFDVS SFNPHGISTF
TDEDNAMYLL VVNHPDAKST VELFKFQEEE KSLLHLKTIR HKLLPNLNDI VAVGPEHFYG
TNDHYFLDPY LQSWEMYLGL AWSYVVYYSP SEVRVVAEGF DFANGINISP DGKYVYIAEL
LAHKIHVYEK HANWTLTPLK SLDFNTLVDN ISVDPETGDL WVGCHPNGMK IFFYDSENPP
ASEVLRIQNI LTEEPKVTQV YAENGTVLQG STVASVYKGK LLIGTVFHKA LYCEL
//

MIM 168820
*RECORD*
*FIELD* NO
168820
*FIELD* TI
+168820 PARAOXONASE 1; PON1
;;PON;;
PARAOXONASE, PLASMA;;
ARYLESTERASE;;
ESTERASE A; ESA
read morePON1 ENZYME ACTIVITY, VARIATION IN, INCLUDED;;
ORGANOPHOSPHATE POISONING, SUSCEPTIBILITY TO, INCLUDED;;
CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED;;
CORONARY ARTERY SPASM 2, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX

DESCRIPTION

The paraoxonase (PON) gene family includes 3 genes, PON1, PON2 (602447),
and PON3 (602720), aligned next to each other on chromosome 7. PON1 (EC
3.1.1.2) hydrolyzes the toxic oxon metabolites of several
organophosphorous insecticides, including parathion, diazinon, and
chlorpyrifos, as well as nerve agents, such as sarin and soman. PON1
also hydrolyzes aromatic esters, preferably those of acetic acid. In
addition, PON1 hydrolyzes a variety of aromatic and aliphatic lactones,
and it also catalyzes the reverse reaction, lactonization, of gamma- and
delta-hydroxycarboxylic acids. Human PON1 is synthesized in liver and
secreted into blood, where it is associated exclusively with high
density lipoproteins (HDLs) and may protect against development of
atherosclerosis (Draganov et al., 2005).

CLONING

Hassett et al. (1991) isolated a full-length PON1 cDNA from a human
liver cDNA library using rabbit Pon1 as a hybridization probe. The
deduced PON1 protein contains 355 amino acids and is more than 85%
similar to the rabbit protein. N-terminal sequences derived from
purified rabbit and human PON1 proteins suggested that the PON1 signal
sequence is retained, except for the initiator methionine.
Characterization of the rabbit and human PON1 cDNAs confirmed that the
signal sequences are not processed, except for the N-terminal
methionine.

Using SDS-PAGE, Draganov et al. (2005) found that PON1 appeared as a
doublet of about 39 and 42 kD. However, using nondenaturing PAGE, they
observed human serum PON1 and recombinant PON1 at apparent molecular
masses of 91.9 and 95.6 kD, respectively, suggesting that PON1 forms
dimers. Glycosidase treatment of human serum PON1 suggested that the
secreted form of PON1 contains complex carbohydrates.

Lu et al. (2006) stated that human PON1, PON2, and PON3 have 3 conserved
cysteines. Cys41 and cys351 are predicted to form an intramolecular
disulfide bond, and cys283 is predicted to be involved in antioxidant
activity.

GENE STRUCTURE

Clendenning et al. (1996) characterized a 28-kb contig encompassing 300
bp of 5-prime sequence, the entire coding region, and 2 kb of 3-prime
flanking sequence of the PON1 gene. The structural portion of the
paraoxonase protein is encoded by 9 exons that form the primary
transcript through the use of typical splice donor and acceptor sites.

Sorenson et al. (1995) showed that the Pon1 gene in mice contains 9
exons spanning approximately 25 to 26 kb.

MAPPING

Eiberg and Mohr (1979) presented linkage data. No linkage with any of 19
markers was found by Mueller et al. (1983). Eiberg et al. (1985) showed
that cystic fibrosis (219700) and PON are linked on chromosome 7
(maximum lod 3.70 at theta = 0.07 in males and 0.00 in females)--the
first step in the cloning of the CF gene in 1989. Tsui et al. (1985)
confirmed the PON-CF linkage by finding linkage of PON to a DNA marker
that is also linked to CF. Schmiegelow et al. (1986) found the PON and
CF loci linked with lod score of 3.46 at recombination fraction 0.07 in
males and 0.13 in females. By in situ hybridization, Humbert et al.
(1993) demonstrated that the PON gene maps to chromosome 7q21-q22.
Mochizuki et al. (1998) pointed out that the PON1, PON2, and PON3 genes
are physically linked on chromosome 7q21.3.

Sorenson et al. (1995) mapped the mouse Pon1 gene to the proximal end of
chromosome 6 by interspecific backcross analysis. Li et al. (1997)
likewise mapped the gene to mouse chromosome 6.

GENE FUNCTION

Simpson (1971) found a unimodal distribution of serum arylesterase
activity in 176 individuals. There was no difference in enzyme activity
between sexes, but the level of activity gradually increased with age.
From a study of twins, heritability of arylesterase activity was
estimated to be 74%. Data from parent pairs suggested that, in addition
to genetic and age factors, unknown nongenetic factors substantially
affected enzyme activity.

Eckerson et al. (1983) concluded that arylesterase activity, measured
with phenylacetate as substrate, and paraoxonase activity are determined
by the same gene. They used the designation esterase A for the
paraoxonase/arylesterase enzyme (see HISTORY for information on the
identification and classification of esterases). Furlong et al. (1991)
also demonstrated that both arylesterase and paraoxonase activities are
expressed by a single enzyme.

Furlong et al. (1988) studied hydrolysis of an insecticide metabolite,
chlorpyrifos oxon, by PON1.

The physiologic role of paraoxonase in detoxication and in intermediary
metabolism is uncertain (La Du, 1988). However, animal studies,
including examination of quantitative adequacy of PON and protection
against paraoxon toxicity, correlation of LD50 values with PON levels,
and demonstration that intravenously injected PON provides protection
against paraoxon toxicity, indicate that serum PON is protective against
organophosphate poisoning (reviewed by Humbert et al., 1993).

In a series of animal experiments, Navab et al. (1997) demonstrated that
the ratio of Apoj (185430) to Pon was increased in fatty
streak-susceptible mice fed an atherogenic diet, in Apoe knockout mice
on a chow diet, in LDL receptor (LDLR; 606945) knockout mice on a
cholesterol-enriched diet, and in fatty streak-susceptible mice injected
with mildly oxidized LDL fed a chow diet. Human studies showed that the
APOJ/PON ratio was significantly higher than that of controls in 14
normolipidemic patients with coronary artery disease in whom the
cholesterol/HDL ratio did not differ significantly from that of
controls.

Draganov et al. (2005) found that glycosylation of recombinant PON1 with
high-mannose-type sugars did not alter its enzymatic activity, but it
may have affected protein stability. They found that PON1, PON2, and
PON3, whether expressed in insect or HEK293 cells, metabolized oxidized
forms of arachidonic acid and docosahexaenoic acid. Otherwise, the PONs
showed distinctive substrate specificities. PON1, but not other PONs,
specifically hydrolyzed organophosphates. About 60% of total
arylesterase and lactonase activity of PON1-transfected HEK293 cells was
secreted into the culture medium. Draganov et al. (2005) found that
recombinant PONs did not protect human LDL against Cu(2+)-induced
oxidation in vitro, and no antioxidant activity copurified with any of
the PONs. They stated that they had previously copurified antioxidant
activity with human serum PON1, but that it was attributable to a low
molecular mass contaminant and to the detergent in the preparation.

MOLECULAR GENETICS

- Variation in PON1 Enzyme Activity

Geldmacher-von Mallinckrodt et al. (1973) first found polymorphism of
paraoxonase activity.

Playfer et al. (1976) found bimodality for plasma paraoxonase activity
in British and Indian persons, defining low and high activity
phenotypes. Study of 40 British families confirmed this genetic
polymorphism. Two phenotypes controlled by 2 alleles at 1 autosomal
locus were defined. The frequency of the low activity phenotype was
lower in the Indian population than in the British population. Malay,
Chinese, and African populations failed to show clear bimodality.
Possibly multiple alleles are present in these populations and result in
a continuous distribution.

Mueller et al. (1983) described a test based on the differential
inhibition of EDTA of plasma paraoxonase from persons with the high
activity allele. With this test, trimodality of activity levels was
suggested by population studies. The gene frequency of the low activity
allele in 531 Seattle blood donors of European origin was 0.72. Family
studies were consistent with codominant autosomal inheritance of 2
alleles encoding products with low and high activity levels.

Eckerson et al. (1983) could clearly distinguish heterozygotes from both
homozygous phenotypes on the basis of the ratio of paraoxonase to
arylesterase activities.

Ortigoza-Ferado et al. (1984) concluded that albumin has paraoxonase
activity and proposed that an optimal assay of polymorphic paraoxonase
activity should be based on activity of the nonalbumin fraction.

Nielsen et al. (1986) reexamined extensive family data and reaffirmed
that segregation into high and low paraoxonase activity is largely or
exclusively due to a 1-locus system.

Humbert et al. (1993) found that arginine at position 192 of PON1
specifies high-activity plasma paraoxonase, whereas glutamine at this
position specifies a low-activity variant (Q192R; 168820.0001). This
polymorphism is also referred to as gln191 to arg. Adkins et al. (1993)
demonstrated that glutamine or arginine at amino acid 191 determines the
A and B allozymes, respectively, of PON1.

In a study of 376 white individuals, Brophy et al. (2001) determined the
genotypes of 3 regulatory region polymorphisms and examined their effect
on plasma PON1 levels as indicated by rates of phenylacetate hydrolysis.
The -108C-T polymorphism (168820.0003) had a significant effect on PON1
activity level, whereas a polymorphism at position -162 had a lesser
effect. A polymorphism at position -909, which is in linkage
disequilibrium with the other sites, appeared to have little or no
independent effect on PON1 activity level in vivo. Brophy et al. (2001)
presented evidence that the effect of the L55M (168820.0002)
polymorphism on lowered paraoxonase activity is not due primarily to the
amino acid change itself but to linkage disequilibrium with the -108C-T
regulatory region polymorphism. The L55M polymorphism marginally
appeared to account for 15.3% of the variance in PON1 activity, but this
dropped to 5% after adjustments for the effects of the -108C-T and Q192R
polymorphisms were made. The -108C-T polymorphism accounted for 22.8% of
the observed variability in PON1 expression levels, which was much
greater than that attributable to other PON1 polymorphisms.

Using a validated microsomal expression system of metabolizing enzymes,
Bouman et al. (2011) identified PON1 as the crucial enzyme for the
bioactivation of the antiplatelet drug clopidogrel, with the common
Q192R polymorphism determining the rate of active metabolite formation.
Analysis of patients with coronary artery disease who underwent stent
implantation and received clopidogrel therapy revealed that Q192
homozygotes were more likely to undergo stent thrombosis than patients
with the RR192 or QR192 genotypes (odds ratio, 3.6; p = 0.0003).

- Susceptibility to Organophosphate Poisoning

PON1 hydrolyzes diazinonoxon, the active metabolite of diazinon, which
is an organophosphate used in sheep dip. Cherry et al. (2002) studied
PON1 polymorphisms in 175 farmers with ill health that they attributed
to sheep dip and 234 other farmers nominated by the ill farmers and
thought to be in good health despite having also dipped sheep. They
calculated odds ratios for the Q192R (168820.0001) and L55M
(168820.0002) polymorphisms, and for PON1 activity with diazinonoxon as
substrate. Cases were more likely than referents to have at least 1 R
allele at position 192 (odds ratio 1.93), both alleles of type LL (odds
ratio 1.70) at position 55, and to have diazoxonase activity below
normal median (odds ratio 1.77). The results supported the hypothesis
that organophosphates contribute to the reported ill health of people
who dip sheep.

- Susceptibility to Coronary Artery Disease

Serrato and Marian (1995), who referred to the gln192-to-arg (Q192R;
168820.0001) polymorphism as the A/G polymorphism or the A/B
polymorphism, demonstrated a relationship to coronary artery disease.
The A and G alleles code for glutamine (A genotype) and arginine (B
genotype), respectively. Individuals with the A genotype have a lower
enzymatic activity than those with the B genotype. Serrato and Marian
(1995) determined the genotypes in 223 patients with angiographically
documented coronary artery disease and in 247 individuals in the general
population. The distribution of genotypes was in Hardy-Weinberg
equilibrium in both groups. Genotypes A and B were present in 49% and
11% of control individuals and in 30% and 18% of patients with coronary
artery disease, respectively (p = 0.0003). The frequency of the A allele
was 0.69 in controls and 0.56 in patients (p = 0.0001). There was no
difference in the distribution of PON genotypes in the subgroups of
patients with restenosis, myocardial infarction, or any of the
conventional risk factors for coronary artery disease as compared with
corresponding subgroups.

The L55M and Q192R polymorphisms in the PON1 gene and the ser311-to-cys
(S311C; 602447.0001) polymorphism in the PON2 gene are associated with
the risk of coronary artery disease in several European or
European-derived populations. Chen et al. (2003) examined the
association between these 3 markers and the severity of coronary artery
disease as determined by the number of diseased coronary artery vessels
in 711 women. No significant association was found between the PON
polymorphisms and stenosis severity in either white or black women.
However, among white women, when data were stratified by the number of
diseased vessels, the frequency of the PON codon 192 arg/arg genotype
was significantly higher in the group with 3-vessel disease than in the
other groups (those with 1-vessel and 2-vessel disease) combined.
Similarly, the frequency of the PON2 codon 311 cys/cys genotype was
significantly higher in the group with 3-vessel disease than in the
other groups combined. The adjusted odds ratio for the development of
3-vessel disease was 2.80 for PON1 codon 192 arg/arg and 3.68 for PON2
codon 311 cys/cys. The data indicated that the severity of coronary
artery disease, in terms of the number of diseased vessels, may be
affected by common genetic variation in the PON gene cluster on
chromosome 7.

Garin et al. (1997) identified homozygosity for the leu54 allele of PON1
(168820.0002), which is associated with high paraoxonase activity, as an
independent risk factor for cardiovascular disease. A linkage
disequilibrium was apparent between the polymorphisms giving rise to
leu54 and arg191. Garin et al. (1997) stated that their study underlined
the fact that susceptibility to cardiovascular disease correlated with
high-activity paraoxonase alleles. Linkage disequilibrium could explain
the association between both the leu54 and the arg191 polymorphisms and
cardiovascular disease.

- Susceptibility to Coronary Artery Spasm

Ito et al. (2002) found that the incidence of the PON1 192R allele was
significantly higher in a cohort of 214 Japanese patients with coronary
spasm than in 212 control subjects. They speculated that the high
frequency of the PON1 arg192 allele may be related to the higher
prevalence of coronary spasm among Japanese than among Caucasians.

- Susceptibility to Microvascular Complications of Diabetes
5

Kao et al. (1998) found an association between the L55M polymorphism in
the PON1 gene (168820.0002) and diabetic retinopathy (MVCD5; 603933) in
patients with type 1 diabetes (222100).

Kao et al. (2002) confirmed the association between L55M and diabetic
retinopathy, finding increased susceptibility for retinopathy with the
leu/leu genotype (odds ratio 3.34; p less than 0.0001).

- Other Associations

Ikeda et al. (2001) found that the distribution of the Q192R and L55M
(168820.0002) polymorphisms in the PON1 gene was significantly different
between Japanese patients with exudative age-related macular
degeneration (ARMD; see 153800) and age- and sex-matched controls. The
BB genotype at position 192 and the LL genotype at position 55 occurred
at higher frequency in patients with ARMD compared to controls (p =
0.0127 and p = 0.0090, respectively). The mean oxidized LDL level in
patients was significantly higher than in controls (p less than 0.01).
Ikeda et al. (2001) concluded that the PON1 gene polymorphisms might
represent a genetic risk factor for ARMD and that increased plasma
oxidized LDL might be involved in the pathogenesis of ARMD.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

GENOTYPE/PHENOTYPE CORRELATIONS

Davies et al. (1996) analyzed the paraoxonase catalytic activity against
the toxic oxon forms which result from the bioactivation of the
organophosphorus insecticides parathion, chloropyrifos, and diazinon in
the P450 system. They also analyzed the hydrolytic activity of PON1
against the nerve agents soman and sarin. Davies et al. (1996) reported
a simple enzyme analysis that provided a clear resolution of PON1
genotypes and phenotypes. The plot of diazoxon hydrolysis versus
paraoxon hydrolysis clearly resolved all 3 genotypes (Q192Q192,
Q191R192, R192R192; see 168820.0001) and at the same time provided
important information about the level of enzyme activity in an
individual. They observed the reversal of the effect of PON1
polymorphisms for diazoxon hydrolysis relative to paraoxon hydrolysis.
RR homozygotes (high paraoxonase activity) had lower diazoxonase
activity than the QQ homozygotes (low paraoxonase activity). They
reported that the effect was also reversed for the nerve gases soman and
sarin (sarin was the nerve gas released in the Tokyo subway in March
1995). The mean value of sarin hydrolysis was only 38 U per liter for
the R192 homozygotes compared with 355 U per liter for the Q192
homozygotes. Davies et al. (1996) observed an increased frequency for
the R192 allele (0.41) in the Hispanic population compared with a
frequency of 0.31 for populations of northern European origin. These
frequencies result in approximately 16% of individuals of Hispanic
origin being homozygous for the R192 PON1 isoform compared with 9% of
individuals of northern European origin. They noted that newborns have
very low activities of PON1, leading them to predict that newborns would
be significantly more sensitive to organophosphorus compounds than
adults. The authors cited studies showing that injected PON1 protects
against organophosphorus poisoning in rodents (Li et al., 1995).

Phuntuwate et al. (2005) studied the activity of 4 PON1 polymorphisms
towards paraoxon, phenylacetate, and diazoxon. They found that the L55M,
Q192R, and -909G-C polymorphisms significantly and variably affected
serum PON1 activity towards the substrates, whereas the -108C-T
polymorphism had no significant effect on serum PON1 activity towards
any substrate. Phuntuwate et al. (2005) suggested that the physiologic
relevance of the PON1 polymorphisms is that they are associated with
significant differences in serum PON1 activity that are substrate
dependent.

Mackness et al. (1998) examined the effects of the 2 common
polymorphisms in PON1 on the ability of HDL to protect LDL from
oxidative modification. HDL protected LDL from oxidative modification,
whatever the combination of PON1 alloenzymes present in it. However, HDL
from QQ/MM homozygotes was most effective in protecting LDL, while HDL
from RR/LL homozygotes was least effective. Thus after 6 hours of
coincubation of HDL and LDL with Cu(2+), PON1-QQ HDL retained 57 +/-
6.3% of its original ability to protect LDL from oxidative modification,
while PON1-QR HDL retained less at 25.1 +/- 4.5% and PON1-RR HDL
retained only 0.75 +/- 0.40%. In similar experiments, HDL from LL and LM
genotypes retained 21.8 +/- 7.5% and 29.5 +/- 6.6%, respectively, of
their protective ability, whereas PON1-MM HDL maintained 49.5 +/- 5.3%.
PON1 polymorphisms may affect the ability of HDL to impede the
development of atherosclerosis and to prevent inflammation.

ANIMAL MODEL

To study the role of PON1 in vivo, Shih et al. (1998) created
Pon1-knockout mice by gene targeting. Compared with their wildtype
littermates, Pon1-deficient mice were extremely sensitive to the toxic
effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and
were more sensitive to chlorpyrifos itself. HDLs isolated from
Pon1-deficient mice were unable to prevent LDL oxidation in a cocultured
cell model of the artery wall, and both HDLs and LDLs isolated from
Pon1-knockout mice were more susceptible to oxidation by cocultured
cells than were lipoproteins from wildtype littermates. When fed on a
high-fat, high-cholesterol diet, Pon1-null mice were more susceptible to
atherosclerosis than were their wildtype littermates.

Watson et al. (2001) identified a serum paraoxonase polymorphism in
rabbit with functional characteristics similar to those of human Q192R.
They suggested that the rabbit may serve as a model in examining the
effect of human PON1 polymorphisms in disease development.

HISTORY

- Identification and Classification of Esterases

Using azo dye coupling techniques and electrophoresis, Tashian (1965)
defined several different esterases in human red cells. Three main
groups, differing as to electrophoretic properties, substrate
specificities and inhibition characteristics, were A, B, and C
esterases. Variants of esterase A were reported by Tashian and Shaw
(1962) and Tashian (1965).

Using starch-gel electrophoresis, Coates et al. (1975) identified
multiple esterase isozymes in every human tissue, and they characterized
the isozymes in terms of electrophoretic mobility, tissue distribution,
developmental changes in utero, substrate specificity, inhibition
properties, and molecular weight. On these criteria, 13 sets of esterase
isozymes were identified, in addition to the esterase isozymes due to
cholinesterase and carbonic anhydrase. The data suggested that the 13
sets of isozymes are determined by at least 9 different genes. The
acetylesterases, which prefer acetate esters as substrates, were divided
into 9 sets of isozymes, designated ESA1 to ESA7, ESC (133270), and ESD
(133280). Coates et al. (1975) divided the butyrylesterases, which
prefer butyrate esters as substrates, into 4 sets of isozymes,
designated ESB1 to ESB4.

*FIELD* AV
.0001
PON1 ENZYME ACTIVITY, VARIATION IN
CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED;;
CORONARY ARTERY SPASM 2, SUSCEPTIBILITY TO, INCLUDED
PON1, GLN192ARG

Humbert et al. (1993) found that arginine at position 192 of PON1
specifies high-activity plasma paraoxonase, whereas glutamine at this
position specifies a low-activity variant. They showed that
allele-specific probes or restriction enzyme analysis of amplified DNA
could be used for genotyping of individuals. This polymorphism is also
referred to as GLN191ARG. Adkins et al. (1993) also demonstrated that
glutamine or arginine at amino acid 191 determines the A and B
allozymes, respectively, of PON1.

Serrato and Marian (1995), who referred to the gln192-to-arg (Q192R)
polymorphism as the A/G polymorphism or the A/B polymorphism,
demonstrated a relationship to coronary artery disease. The A and G
alleles code for glutamine (A genotype) and arginine (B genotype),
respectively. Individuals with the A genotype have a lower enzymatic
activity than those with the B genotype. Serrato and Marian (1995)
determined the genotypes in 223 patients with angiographically
documented coronary artery disease and in 247 individuals in the general
population. The distribution of genotypes was in Hardy-Weinberg
equilibrium in both groups. Genotypes A and B were present in 49% and
11% of control individuals and in 30% and 18% of patients with coronary
artery disease, respectively (p = 0.0003). The frequency of the A allele
was 0.69 in controls and 0.56 in patients (p = 0.0001). There was no
difference in the distribution of PON genotypes in the subgroups of
patients with restenosis, myocardial infarction, or any of the
conventional risk factors for coronary artery disease as compared with
corresponding subgroups.

Antikainen et al. (1996) referred to this polymorphism as gln191 to arg
(Q191R). In Finns they were unable to confirm an association with the
risk of coronary artery disease. The most common genotype found in both
380 well-characterized CAD patients and 169 controls was AA (gln/gln).
The frequency of the A allele was 0.74 in both patients and controls.
The genotype distributions of the 2 groups did not differ and were
similar to those reported earlier in other caucasoid populations.

Odawara et al. (1997) performed an association study of the arg192
polymorphism with coronary heart disease (CHD) in Japanese
noninsulin-dependent diabetes mellitus (NIDDM; 125853) subjects. They
genotyped 164 NIDDM patients (42 with and 122 without CHD). Other known
risk factors for CHD were matched between the 2 groups. AB + BB isoforms
were detected in 41 of 42 NIDDM patients with CHD. The proportion of B
allele carriers (AB + BB) was significantly higher than that of AA
carriers among NIDDM patients with CHD compared to those without CHD
(chi square = 7.68, p = 0.003). Multivariate logistic regression
analyses showed an increased odds ratio (8.8; CI, 1.1-69) in B allele
carriers, while odds ratios of other risk factors remained between 1.0
and 1.9. The authors concluded that Japanese NIDDM patients who are
carriers of the B allele of the gln192-to-arg polymorphism have an
increased risk for developing CHD independent of other known risk
factors for CHD.

The arg192 isoform of paraoxonase hydrolyzes paraoxon more rapidly than
the gln192 isoform. However, with respect to hydrolysis of toxic nerve
agents, such as sarin, the arg192 isoform displays a lower activity than
the other isoform. Yamasaki et al. (1997) found that the arg192 allele
is more common in the Japanese (allele frequency, 0.66) than in people
of other races (range, 0.24 to 0.31). In Japanese, 41.4% of subjects
were homozygous for the arg192 allele, which shows a very low hydrolysis
activity for sarin. Thus, there seems to be a racial difference in
vulnerability to toxic nerve agents, such as sarin. The dominance of the
arg192 allele in the Japanese population probably worsened the tragedy
of March 1995 in the Tokyo subway.

Heinecke and Lusis (1998) reviewed the results of previous studies of
the PON1 Q192R polymorphism in CHD and raised the question of whether
these PON polymorphisms support the oxidative damage hypothesis of
atherosclerosis.

Paolisso et al. (2001) investigated the relationship between a PON1
polymorphism and brachial reactivity in healthy adult subjects in the
presence of acute hypertriglyceridemia as a prooxidant factor. In 101
healthy subjects the response to flow-induced vasodilation was measured
before and after Intralipid infusion. In the same subjects the A/B PON1
polymorphism was genotyped. The frequency was 0.545 for the AA genotype,
0.356 for the AB genotype, and 0.099 for the BB genotype. At baseline
all genotype groups had similar increases in brachial artery diameter
and flow. After Intralipid infusion, subjects sharing the BB genotype
had a significant decrease versus baseline values in changes in brachial
artery diameter, but not in flow. In a subgroup of 55 subjects
distributed along the 3 PON1 genotypes the same study protocol was
repeated by buccal nitroglycerine administration to study the
endothelium-independent vasodilation. Again, subjects with the BB
genotype had the worse vasodilation. The authors concluded that
transient hypertriglyceridemia decreases vascular reactivity more in
subjects with the PON1 BB genotype than in those with the other PON1
genotypes.

Ito et al. (2002) found that the incidence of the PON1 192R allele was
significantly higher in a cohort of 214 Japanese patients with coronary
spasm than in 212 control subjects. They speculated that the high
frequency of the PON1 arg192 allele may be related to the higher
prevalence of coronary spasm among Japanese than among Caucasians. They
also noted that cigarette smoking reduces serum PON1 activity in
patients with coronary artery disease, and that cigarette smoking is
highly prevalent in the Japanese.

PON1 hydrolyzes diazinonoxon, the active metabolite of diazinon, which
is an organophosphate used in sheep dip. Cherry et al. (2002) studied
PON1 polymorphisms in 175 farmers with ill health that they attributed
to sheep dip and 234 other farmers nominated by the ill farmers and
thought to be in good health despite having also dipped sheep. They
calculated odds ratios for the Q192R and L55M (168820.0002)
polymorphisms, and for PON1 activity with diazinonoxon as substrate.
Cases were more likely than referents to have at least 1 R allele at
position 192 (odds ratio 1.93), both alleles of type LL (odds ratio
1.70) at position 55, and to have diazoxonase activity below normal
median (odds ratio 1.77). The results supported the hypothesis that
organophosphates contribute to the reported ill health of people who dip
sheep.

Bonafe et al. (2002) examined the Q192R polymorphism in 308 Italian
unrelated centenarians and 579 Italian individuals aged 20 to 65 years.
The percentage of carriers of the R192 allele was significantly higher
in centenarians than in young people (0.539 vs 0.447, p = 0.011). No
significant difference between centenarians and young individuals was
observed for the PON1 L55M polymorphism (168820.0002). The authors
proposed that the R192 allele decreases mortality in carriers, but that
the effect of PON1 variability on the overall population mortality is
rather slight. The findings suggested that PON1 is one of the genes
affecting the individual adaptive capacity and is therefore one of the
genes affecting rate and quality of aging (152430).

In a longitudinal study of survival involving 1,932 Danish individuals,
Christiansen et al. (2004) found that women homozygous for the R192
allele had a poorer survival rate compared to Q192 homozygotes (hazard
ratio, 1.38; p = 0.04). An independent sample of 541 Danish individuals
confirmed the findings for R192 homozygous women, with a hazard ratio of
1.38 (p = 0.09). Combining the 2 samples did not change the risk
estimate, but increased the statistical significance (p = 0.008). Using
self-reported data on ischemic heart disease, the authors found only a
nonsignificant trend of R192 homozygosity in women being a risk factor.
Christiansen et al. (2004) concluded that PON1 R192 homozygosity is
associated with increased mortality in women in the second half of life
and that this increased mortality is possibly related to CHD severity
and survival after CHD rather than susceptibility to the development of
CHD.

Using a validated microsomal expression system of metabolizing enzymes,
Bouman et al. (2011) identified PON1 as the crucial enzyme for the
bioactivation of the antiplatelet drug clopidogrel, with the common
Q192R polymorphism determining the rate of active metabolite formation.
A case-cohort study of individuals with coronary artery disease who
underwent stent implantation and received clopidogrel therapy revealed
that Q192 homozygotes were more likely to undergo stent thrombosis than
patients with the RR192 or QR192 genotypes (odds ratio, 3.6; p =
0.0003). In addition, PON1 QQ192 homozygotes showed a considerably
higher risk than RR192 homozygotes of lower PON1 plasma activity, lower
plasma concentrations of active metabolite, and lower platelet
inhibition.

.0002
PON1 ENZYME ACTIVITY, VARIATION IN
CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED;;
MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 5, INCLUDED
PON1, LEU55MET

This polymorphism was originally designated MET54LEU (M54L; Garin et
al., 1997) and has also been designated MET55LEU (M55L; e.g., Kao et
al., 1998, 2002). It is referred to here as LEU55MET (L55M) because
Brophy et al. (2001) noted that leucine is the more frequent amino acid
at position 55 (or 54, depending on the numbering system).

Garin et al. (1997) investigated this polymorphism in 408 diabetic
patients with or without vascular disease. There were highly significant
differences in plasma concentrations and activities of paraoxonase
between genotypes defined by the met54-to-leu polymorphism. On the other
hand, the arg191 variant (168820.0001) had little impact on paraoxonase
concentration. Homozygosity for the leu54 allele was an independent risk
factor for cardiovascular disease. A linkage disequilibrium was apparent
between the mutations giving rise to leu54 and arg191. Garin et al.
(1997) stated that their study underlined the fact that susceptibility
to cardiovascular disease correlated with high-activity paraoxonase
alleles. The M54L polymorphism appeared to be of central importance to
paraoxonase function by virtue of its association with modulated
concentrations. Linkage disequilibrium could explain the association
between both the leu54 and the arg191 polymorphisms and CVD.

Brophy et al. (2001) presented evidence that the L55M effect of lowered
activity is not due primarily to the amino acid change itself but to
linkage disequilibrium with the -108 regulatory region polymorphism
(168820.0003). The -108C/T polymorphism accounted for 22.8% of the
observed variability in PON1 expression levels, which was much greater
than that attributable to other PON1 polymorphisms.

Deakin et al. (2002) analyzed glucose metabolism as a function of PON1
polymorphisms in young healthy nondiabetic men from families with
premature coronary heart disease (CHD) and matched controls. The L55M
PON1 polymorphism was independently associated with the glucose response
to an oral glucose tolerance test. LL homozygotes had significantly
impaired glucose disposal (p = 0.0007) compared with LM and MM
genotypes. It was particularly marked for subjects from high CHD risk
families and differentiated them from matched controls (p = 0.049). The
area under the glucose curve (p = 0.0036) and the time to peak glucose
value (p = 0.026) were significantly higher in the LL carriers, whereas
the insulin response was slower (p = 0.013). The results showed that an
association exists between PON1 gene polymorphisms and glucose
metabolism. The authors also concluded that the L55M-glucose interaction
differentiated offspring of high CHD risk families, suggesting that it
may be of particular relevance for vascular disease and possibly other
diabetic complications.

Barbieri et al. (2002) investigated association of the M54L polymorphism
with the degree of insulin resistance (IR) in 213 healthy subjects by
the homeostasis model assessment. The frequency was 0.366 for the LL
genotype, 0.469 for the LM genotype, and 0.164 for the MM genotype.
Comparing the 3 genotype groups, LL genotype had the more severe degree
of IR. Subjects carrying the LL genotype were associated with the IR
syndrome picture more than individuals carrying the M allele because
they were more overweight and had the highest levels of triglycerides
and blood pressure and the lowest values of plasma high density
lipoprotein cholesterol. In a multivariate stepwise regression analysis,
LL genotype was a significant predictor of IR, independent of age, sex,
body mass index, fasting plasma triglycerides, and high density
lipoprotein cholesterol. The authors concluded that the presence of LL
PON genotype is associated with a more severe degree of IR. Thus, IR
might be the possible missing link between the M54L polymorphism and the
increased cardiovascular risk.

Kao et al. (1998) investigated the potential significance of these PON1
polymorphisms in the pathogenesis of diabetic retinopathy in IDDM
(MVCD5; 612633). They analyzed samples from 80 patients with diabetic
retinopathy and 119 controls. The allelic frequency of the leu54 (L)
polymorphism was significantly higher in the group with retinopathy than
in the group without retinopathy (73% vs 57%, p less than 0.001). Kao et
al. (1998) concluded that the genotype L/L was strongly associated with
the development of diabetic retinopathy (p less than 0.001), but a
similar association was not found with the arg192 polymorphism.

Kao et al. (2002) analyzed the M54L PON1 polymorphism in 372 adolescents
with type 1 diabetes (222100) and confirmed increased susceptibility to
diabetic retinopathy with the leu/leu genotype (odds ratio, 3.4; p less
than 0.0001) independent of age, duration of disease, and cholesterol.

.0003
PON1 ENZYME ACTIVITY, VARIATION IN
PON1, -108C-T

Brophy et al. (2001) concluded that the -108C/T polymorphism in the
5-prime regulatory region of the PON1 gene accounts for 22.8% of the
observed variability in PON1 expression levels, which is much greater
than that attributable to other PON1 polymorphisms.

*FIELD* SA
Augustinsson and Henricson (1966); Eckerson et al. (1983); Geldmacher-von
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Castellani, L. W.; Furlong, C. E.; Costa, L. G.; Fogelman, A. M.;
Lusis, A. J.: Mice lacking serum paraoxonase are susceptible to organophosphate
toxicity and atherosclerosis. Nature 394: 284-287, 1998.

51. Simpson, N. E.: Serum arylesterase levels of activity in twins
and their parents. Am. J. Hum. Genet. 23: 375-382, 1971.

52. Sorenson, R. C.; Primo-Parmo, S. L.; Camper, S.; La Du, B. N.
: The genetic mapping and gene structure of mouse paraoxonase/arylesterase. Genomics 30:
431-438, 1995.

53. Tashian, R. E.: Genetic variation and evolution of the carboxylic
esterases and carbonic anhydrases of primate erythrocytes. Am. J.
Hum. Genet. 17: 257-272, 1965.

54. Tashian, R. E.; Shaw, M. W.: Inheritance of an erythrocyte acetylesterase
variant of man. Am. J. Hum. Genet. 14: 295-300, 1962.

55. Tsui, L.-C.; Buchwald, M.; Barker, D.; Braman, J. C.; Knowlton,
R.; Schumm, J. W.; Eiberg, H.; Mohr, J.; Kennedy, D.; Plavsic, N.;
Zsiga, M.; Markiewicz, D.; Akots, G.; Brown, V.; Helms, C.; Gravius,
T.; Parker, C.; Rediker, K.; Donis-Keller, H.: Cystic fibrosis locus
defined by a genetically linked polymorphic DNA marker. Science 230:
1054-1057, 1985.

56. Watson, C. E.; Draganov, D. I.; Billecke, S. S.; Bisgaier, C.
L.; La Du, B. N.: Rabbits possess a serum paraoxonase polymorphism
similar to the human Q192R. Pharmacogenetics 11: 123-134, 2001.

57. Yamasaki, Y.; Sakamoto, K.; Watada, H.; Kajimoto, Y.; Hori, M.
: The arg-192 isoform of paraoxonase with low sarin-hydrolyzing activity
is dominant in the Japanese. Hum. Genet. 101: 67-68, 1997.

*FIELD* CS

Misc:
Organophosphate poisoning sensitvity

Lab:
Low paroxonase (arylesterase hydrolyzing paroxon to produce p-nitrophenol)

Inheritance:
Autosomal dominant (7q21-q22)

*FIELD* CN
Marla J. F. O'Neill - updated: 8/25/2011
Marla J. F. O'Neill - updated: 6/22/2010
Marla J. F. O'Neill - updated: 2/19/2009
Matthew B. Gross - reorganized: 11/6/2008
Matthew B. Gross - updated: 11/6/2008
Patricia A. Hartz - updated: 10/29/2008
Marla J. F. O'Neill - updated: 8/30/2006
Jane Kelly - updated: 8/1/2005
Marla J. F. O'Neill - updated: 11/8/2004
Victor A. McKusick - updated: 1/22/2003
Michael B. Petersen - updated: 1/15/2003
John A. Phillips, III - updated: 7/30/2002
John A. Phillips, III - updated: 7/29/2002
John A. Phillips, III - updated: 7/26/2002
Victor A. McKusick - updated: 4/8/2002
Victor A. McKusick - updated: 1/25/2002
John A. Phillips, III - updated: 10/1/2001
Victor A. McKusick - updated: 6/20/2001
Victor A. McKusick - updated: 5/18/2001
Ada Hamosh - updated: 5/11/1999
John A. Phillips, III - updated: 1/7/1999
Victor A. McKusick - updated: 8/26/1998
Victor A. McKusick - updated: 7/13/1998
Victor A. McKusick - updated: 10/14/1997
Michael J. Wright - updated: 9/25/1997
John A. Phillips, III - updated: 9/12/1997
Victor A. McKusick - updated: 8/19/1997
Victor A. McKusick - updated: 2/6/1997
Moyra Smith - updated: 11/20/1996
Alan F. Scott - updated: 2/27/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 09/14/2012
carol: 12/22/2011
carol: 8/25/2011
terry: 8/25/2011
wwang: 6/28/2010
terry: 6/22/2010
wwang: 1/13/2010
ckniffin: 12/29/2009
ckniffin: 7/30/2009
alopez: 4/2/2009
carol: 2/23/2009
terry: 2/19/2009
alopez: 12/16/2008
mgross: 11/6/2008
terry: 10/29/2008
carol: 10/10/2007
alopez: 3/27/2007
carol: 9/5/2006
terry: 8/30/2006
alopez: 8/1/2005
terry: 2/18/2005
tkritzer: 11/11/2004
tkritzer: 11/8/2004
carol: 7/6/2004
joanna: 3/17/2004
tkritzer: 1/31/2003
tkritzer: 1/22/2003
terry: 1/22/2003
cwells: 1/15/2003
tkritzer: 7/31/2002
tkritzer: 7/30/2002
tkritzer: 7/29/2002
tkritzer: 7/26/2002
cwells: 4/19/2002
cwells: 4/15/2002
terry: 4/8/2002
carol: 2/21/2002
carol: 2/15/2002
mcapotos: 2/6/2002
terry: 1/25/2002
alopez: 10/1/2001
carol: 10/1/2001
mcapotos: 6/26/2001
mcapotos: 6/21/2001
terry: 6/20/2001
mcapotos: 5/25/2001
terry: 5/18/2001
carol: 5/20/1999
alopez: 5/14/1999
terry: 5/11/1999
alopez: 4/7/1999
alopez: 1/7/1999
carol: 8/27/1998
terry: 8/26/1998
alopez: 7/15/1998
terry: 7/13/1998
alopez: 3/16/1998
alopez: 11/19/1997
alopez: 11/11/1997
alopez: 11/6/1997
jenny: 10/21/1997
terry: 10/14/1997
dholmes: 10/2/1997
dholmes: 10/1/1997
dholmes: 9/22/1997
terry: 8/19/1997
mark: 3/16/1997
terry: 2/6/1997
terry: 1/24/1997
jamie: 11/22/1996
mark: 11/20/1996
mark: 10/16/1996
terry: 10/9/1996
terry: 9/10/1996
terry: 8/23/1996
terry: 4/17/1996
mark: 2/27/1996
mark: 1/27/1996
terry: 1/19/1996
mimadm: 1/14/1995
davew: 7/14/1994
warfield: 3/3/1994
carol: 1/28/1993
carol: 11/12/1992
carol: 11/9/1992

MIM 612633
*RECORD*
*FIELD* NO
612633
*FIELD* TI
#612633 MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 5; MVCD5
;;RETINOPATHY, DIABETIC, SUSCEPTIBILITY TO
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
susceptibility to microvascular complications of diabetes-5 is
associated with variation in the PON1 gene (168820) on chromosome
7q21.3.

For a discussion of genetic heterogeneity of susceptibility to
microvascular complications of diabetes, see MVCD1 (603933).

MOLECULAR GENETICS

Kao et al. (1998) analyzed the L55M polymorphism in the PON1 gene
(168820.0002), which they designated M54L, in 80 patients with diabetic
retinopathy and 119 controls, and found a significantly higher allelic
frequency of the leu55 polymorphism in the group with retinopathy than
in the group without retinopathy (73% vs 57%, p less than 0.001).

Brophy et al. (2001) presented evidence that the L55M effect of lowered
activity is not due primarily to the amino acid change itself but to
linkage disequilibrium with the -108 regulatory region polymorphism
(168820.0003). The -108C/T polymorphism accounted for 22.8% of the
observed variability in PON1 expression levels, which was much greater
than that attributable to other PON1 polymorphisms.

Kao et al. (2002) analyzed the L55M (M54L) PON1 polymorphism and the
C311S PON2 polymorphism (602447.0001) in 372 adolescents with type 1
diabetes (222100) who were also assessed for diabetic retinopathy and
albumin excretion rate. The authors confirmed the increased
susceptibility to diabetic retinopathy with the PON1 leu/leu genotype
(odds ratio, 3.4; p less than 0.0001) independent of age, duration of
disease, and cholesterol, and found that the PON2 ser/ser genotype was
significantly more common in patients with microalbuminuria (odds ratio,
4.72; p less than 0.0001). The authors also observed strong linkage
disequilibrium between PON2 ser311 and PON1 leu55 that was greater in
those without either complication, suggesting that retinopathy and
nephropathy may have distinct genetic susceptibility.

*FIELD* RF
1. Brophy, V. H.; Jampsa, R. L.; Clendenning, J. B.; McKinstry, L.
A.; Jarvik, G. P.; Furlong, C. E.: Effects of 5-prime regulatory-region
polymorphisms on paraoxonase-gene (PON1) expression. Am. J. Hum.
Genet. 68: 1428-1436, 2001.

2. Kao, Y.; Donaghue, K. C.; Chan, A.; Bennetts, B. H.; Knight, J.;
Silink, M.: Paraoxonase gene cluster is a genetic marker for early
microvascular complications in type 1 diabetes. Diabet. Med. 19:
212-215, 2002.

3. Kao, Y.-L.; Donaghue, K.; Chan, A.; Knight, J.; Silink, M.: A
variant of paraoxonase (PON1) gene is associated with diabetic retinopathy
in IDDM. J. Clin. Endocr. Metab. 83: 2589-2592, 1998.

*FIELD* CD
Marla J. F. O'Neill: 2/23/2009

*FIELD* ED
carol: 02/23/2009