RBCC

Full text data of HPRT1

HPRT1 (HPRT) [Confidence: high (present in two of the MS resources)]
Hypoxanthine-guanine phosphoribosyltransferase; HGPRT; HGPRTase; 2.4.2.8
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00218493
IPI00218493 Hypoxanthine-guanine phosphoribosyltransferase IMP + diphosphate = hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate and GMP + diphosphate = guanine + 5-phospho-alpha-D-ribose 1-diphosphate 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 P00492
ID HPRT_HUMAN Reviewed; 218 AA.
AC P00492; A6NHF0; B2R8M9;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Hypoxanthine-guanine phosphoribosyltransferase;
DE Short=HGPRT;
DE Short=HGPRTase;
DE EC=2.4.2.8;
GN Name=HPRT1; Synonyms=HPRT;
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].
RX PubMed=6300847; DOI=10.1073/pnas.80.2.477;
RA Jolly D.J., Okayama H., Berg P., Esty A.C., Filpula D., Bohlen P.,
RA Johnson G.G., Shively J.E., Hunkapillar T., Friedmann T.;
RT "Isolation and characterization of a full-length expressible cDNA for
RT human hypoxanthine phosphoribosyl transferase.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:477-481(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2341149; DOI=10.1016/0888-7543(90)90493-E;
RA Edwards A., Voss H., Rice P., Civitello A., Stegemann J., Schwager C.,
RA Zimmermann J., Erfle H., Caskey C.T., Ansorge W.;
RT "Automated DNA sequencing of the human HPRT locus.";
RL Genomics 6:593-608(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [7]
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 [8]
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 [9]
RP PROTEIN SEQUENCE OF 2-218.
RX PubMed=7107641;
RA Wilson J.M., Tarr G.E., Mahoney W.C., Kelley W.N.;
RT "Human hypoxanthine-guanine phosphoribosyltransferase. Complete amino
RT acid sequence of the erythrocyte enzyme.";
RL J. Biol. Chem. 257:10978-10985(1982).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-9.
RX PubMed=3023844;
RA Patel P.I., Framson P.E., Caskey C.T., Chinault A.C.;
RT "Fine structure of the human hypoxanthine phosphoribosyltransferase
RT gene.";
RL Mol. Cell. Biol. 6:393-403(1986).
RN [11]
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 [12]
RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) IN COMPLEX WITH GMP.
RX PubMed=8044844; DOI=10.1016/0092-8674(94)90301-8;
RA Eads J.C., Scapin G., Xu Y., Grubmeyer C., Sacchettini J.C.;
RT "The crystal structure of human hypoxanthine-guanine
RT phosphoribosyltransferase with bound GMP.";
RL Cell 78:325-334(1994).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH A
RP TRANSITION-STATE ANALOG.
RX PubMed=10360366; DOI=10.1038/9376;
RA Shi W., Li C.M., Tyler P.C., Furneaux R.H., Grubmeyer C.,
RA Schramm V.L., Almo S.C.;
RT "The 2.0 A structure of human hypoxanthine-guanine
RT phosphoribosyltransferase in complex with a transition-state analog
RT inhibitor.";
RL Nat. Struct. Biol. 6:588-593(1999).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF MUTANT ALA-69 IN COMPLEX WITH
RP PHOSPHORIBOSYLPYROPHOSPHATE; MAGNESIUM IONS AND HYPOXANTHINE ANALOG
RP HPP, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MASS
RP SPECTROMETRY, AND MUTAGENESIS OF LYS-69.
RX PubMed=10338013;
RA Balendiran G.K., Molina J.A., Xu Y., Torres-Martinez J., Stevens R.,
RA Focia P.J., Eakin A.E., Sacchettini J.C., Craig S.P. III;
RT "Ternary complex structure of human HGPRTase, PRPP, Mg2+, and the
RT inhibitor HPP reveals the involvement of the flexible loop in
RT substrate binding.";
RL Protein Sci. 8:1023-1031(1999).
RN [15]
RP REVIEW ON VARIANTS.
RX PubMed=1487231; DOI=10.1007/BF00220062;
RA Sculley D.G., Dawson P.A., Emmerson B.T., Gordon R.B.;
RT "A review of the molecular basis of hypoxanthine-guanine
RT phosphoribosyltransferase (HPRT) deficiency.";
RL Hum. Genet. 90:195-207(1992).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF APOPROTEIN, AND SUBUNIT.
RX PubMed=15990111; DOI=10.1016/j.jmb.2005.05.061;
RA Keough D.T., Brereton I.M., de Jersey J., Guddat L.W.;
RT "The crystal structure of free human hypoxanthine-guanine
RT phosphoribosyltransferase reveals extensive conformational plasticity
RT throughout the catalytic cycle.";
RL J. Mol. Biol. 351:170-181(2005).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) IN COMPLEXES WITH ACYCLIC
RP NUCLEOSIDE PHOSPHONATES, AND CATALYTIC ACTIVITY.
RX PubMed=19527031; DOI=10.1021/jm900267n;
RA Keough D.T., Hockova D., Holy A., Naesens L.M., Skinner-Adams T.S.,
RA Jersey J., Guddat L.W.;
RT "Inhibition of hypoxanthine-guanine phosphoribosyltransferase by
RT acyclic nucleoside phosphonates: a new class of antimalarial
RT therapeutics.";
RL J. Med. Chem. 52:4391-4399(2009).
RN [18]
RP VARIANT GOUT-HPRT TORONTO GLY-51.
RX PubMed=6853490;
RA Wilson J.M., Kobayashi R., Fox I.H., Kelley W.N.;
RT "Human hypoxanthine-guanine phosphoribosyltransferase.";
RL J. Biol. Chem. 258:6458-6460(1983).
RN [19]
RP VARIANT LNS KINSTON ASN-194.
RX PubMed=6853716; DOI=10.1172/JCI110884;
RA Wilson J.M., Kelley W.N.;
RT "Molecular basis of hypoxanthine-guanine phosphoribosyltransferase
RT deficiency in a patient with the Lesch-Nyhan syndrome.";
RL J. Clin. Invest. 71:1331-1335(1983).
RN [20]
RP VARIANT GOUT-HPRT LONDON LEU-110.
RX PubMed=6572373; DOI=10.1073/pnas.80.3.870;
RA Wilson J.M., Tarr G.E., Kelley W.N.;
RT "Human hypoxanthine (guanine) phosphoribosyltransferase: an amino acid
RT substitution in a mutant form of the enzyme isolated from a patient
RT with gout.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:870-873(1983).
RN [21]
RP VARIANT GOUT-HPRT MUNICH ARG-104.
RX PubMed=6706936;
RA Wilson J.M., Kelley W.N.;
RT "Human hypoxanthine-guanine phosphoribosyltransferase. Structural
RT alteration in a dysfunctional enzyme variant (HPRTMunich) isolated
RT from a patient with gout.";
RL J. Biol. Chem. 259:27-30(1984).
RN [22]
RP VARIANT GOUT-HPRT MUNICH ARG-104.
RX PubMed=3358423;
RA Cariello N.F., Scott J.K., Kat A.G., Thilly W.G., Keohavong P.;
RT "Resolution of a missense mutant in human genomic DNA by denaturing
RT gradient gel electrophoresis and direct sequencing using in vitro DNA
RT amplification: HPRT Munich.";
RL Am. J. Hum. Genet. 42:726-734(1988).
RN [23]
RP VARIANT LNS FLINT LEU-74.
RX PubMed=3384338; DOI=10.1016/0378-1119(88)90536-7;
RA Davidson B.L., Pashmforoush M., Kelly W.N., Palella T.D.;
RT "Genetic basis of hypoxanthine guanine phosphoribosyltransferase
RT deficiency in a patient with the Lesch-Nyhan syndrome (HPRTFlint).";
RL Gene 63:331-336(1988).
RN [24]
RP VARIANT LNS MIDLAND ASP-130.
RX PubMed=3265398; DOI=10.1016/0378-1119(88)90601-4;
RA Davidson B.L., Palella T.D., Kelly W.N.;
RT "Human hypoxanthine-guanine phosphoribosyltransferase: a single
RT nucleotide substitution in cDNA clones isolated from a patient with
RT Lesch-Nyhan syndrome (HPRTMidland).";
RL Gene 68:85-91(1988).
RN [25]
RP VARIANT ANN ARBOR.
RX PubMed=2896620; DOI=10.1007/BF00291707;
RA Fujimori S., Hidaka Y., Davidson B.L., Palella T.D., Kelley W.N.;
RT "Identification of a single nucleotide change in a mutant gene for
RT hypoxanthine-guanine phosphoribosyltransferase (HPRT Ann Arbor).";
RL Hum. Genet. 79:39-43(1988).
RN [26]
RP VARIANT GOUT-HPRT LONDON LEU-110.
RX PubMed=3198771; DOI=10.1172/JCI113839;
RA Davidson B.L., Chin S.J., Wilson J.M., Kelley W.N., Palella T.D.;
RT "Hypoxanthine-guanine phosphoribosyltransferase. Genetic evidence for
RT identical mutations in two partially deficient subjects.";
RL J. Clin. Invest. 82:2164-2167(1988).
RN [27]
RP VARIANTS DIRRANBANDI AND YERONGA.
RX PubMed=3148064; DOI=10.1007/BF01800364;
RA Keough D.T., Gordon R.B., Dejersey J., Emmerson B.T.;
RT "Biochemical basis of hypoxanthine-guanine phosphoribosyltransferase
RT deficiency in nine families.";
RL J. Inherit. Metab. Dis. 11:229-238(1988).
RN [28]
RP VARIANTS JAPAN-1 AND JAPAN-2.
RX PubMed=2572141;
RA Igarashi T., Minami M., Nishida Y.;
RT "Molecular analysis of hypoxanthine-guanine phosphoribosyltransferase
RT mutations in five unrelated Japanese patients.";
RL Acta Paediatr. Jpn. Overseas Ed. 31:303-313(1989).
RN [29]
RP VARIANT GOUT-HPRT ASHVILLE GLY-201.
RX PubMed=2909537;
RA Davidson B.L., Pashmforoush M., Kelly W.N., Palella T.D.;
RT "Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The
RT molecular defect in a patient with gout (HPRTAshville).";
RL J. Biol. Chem. 264:520-525(1989).
RN [30]
RP VARIANT LNS YALE ARG-71.
RX PubMed=2910902; DOI=10.1172/JCI113846;
RA Fujimori S., Davidson B.L., Kelley W.N., Palella T.D.;
RT "Identification of a single nucleotide change in the hypoxanthine-
RT guanine phosphoribosyltransferase gene (HPRTYale) responsible for
RT Lesch-Nyhan syndrome.";
RL J. Clin. Invest. 83:11-13(1989).
RN [31]
RP VARIANTS ARLINGEN; DETROIT; NEW BRITON AND NEW HAVEN.
RX PubMed=2738157; DOI=10.1172/JCI114160;
RA Davidson B.L., Tarle S.A., Palella T.D., Kelley W.N.;
RT "Molecular basis of hypoxanthine-guanine phosphoribosyltransferase
RT deficiency in ten subjects determined by direct sequencing of
RT amplified transcripts.";
RL J. Clin. Invest. 84:342-346(1989).
RN [32]
RP VARIANTS RKJ.
RX PubMed=2928313; DOI=10.1073/pnas.86.6.1919;
RA Gibbs R.A., Nguyen P.N., McBride L.J., Koepf S.M., Caskey C.T.;
RT "Identification of mutations leading to the Lesch-Nyhan syndrome by
RT automated direct DNA sequencing of in vitro amplified cDNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:1919-1923(1989).
RN [33]
RP VARIANTS LNS RJK LYS-45; LEU-74; ASP-130; SER-131; LYS-143; SER-161;
RP TYR-177; ASN-194; VAL-199; ASP-204 AND TYR-206.
RX PubMed=2347587; DOI=10.1016/0888-7543(90)90545-6;
RA Gibbs R.A., Nguyen P.N., Edwards A., Civitello A.B., Caskey C.T.;
RT "Multiplex DNA deletion detection and exon sequencing of the
RT hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families.";
RL Genomics 7:235-244(1990).
RN [34]
RP VARIANT LNS MONTREAL THR-57.
RX PubMed=2358296; DOI=10.1007/BF00276334;
RA Skopek T.R., Recio L., Simpson D., Dallaire L., Melancon S.B.,
RA Ogier H., O'Neill J.P., Falta M.T., Nicklas J.A., Albertini R.J.;
RT "Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal)
RT by use of T-lymphocyte cultures.";
RL Hum. Genet. 85:111-116(1990).
RN [35]
RP VARIANT LNS BRISBANE ILE-168.
RX PubMed=2246854; DOI=10.1007/BF01799570;
RA Gordon R.B., Sculley D.G., Dawson P.A., Beacham I.R., Emmerson B.T.;
RT "Identification of a single nucleotide substitution in the coding
RT sequence of in vitro amplified cDNA from a patient with partial HPRT
RT deficiency (HPRTBRISBANE).";
RL J. Inherit. Metab. Dis. 13:692-700(1990).
RN [36]
RP VARIANTS GRAVESEND; MASHAD; HEAPEY; BANBURY; RUNCORN; FARNHAM; MARLOW
RP AND READING.
RX PubMed=2018042;
RA Davidson B.L., Tarle S.A., van Antwerp M., Gibbs D.A., Watts R.W.E.,
RA Kelley W.N., Palella T.D.;
RT "Identification of 17 independent mutations responsible for human
RT hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency.";
RL Am. J. Hum. Genet. 48:951-958(1991).
RN [37]
RP VARIANTS LNS TYR-28 DEL; VAL-50; GLU-70; LEU-74; THR-183 AND ARG-204.
RX PubMed=2071157; DOI=10.1016/0888-7543(91)90341-B;
RA Tarle S.A., Davidson B.L., Wu V.C., Zidar F.J., Seegmiller J.E.,
RA Kelley W.N., Palella T.D.;
RT "Determination of the mutations responsible for the Lesch-Nyhan
RT syndrome in 17 subjects.";
RL Genomics 10:499-501(1991).
RN [38]
RP VARIANTS PERTH; SWAN; TOOWONG AND URANGAN.
RX PubMed=1937471; DOI=10.1007/BF00201727;
RA Sculley D.G., Dawson P.A., Beacham I.R., Emmerson B.T., Gordon R.B.;
RT "Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis
RT of HPRT mutations by direct sequencing and allele-specific
RT amplification.";
RL Hum. Genet. 87:688-692(1991).
RN [39]
RP VARIANT ALA-188, AND NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 183-193.
RX PubMed=1840476;
RA Yamada Y., Goto H., Ogasawara N.;
RT "Identification of two independent Japanese mutant HPRT genes using
RT the PCR technique.";
RL Adv. Exp. Med. Biol. 309B:121-124(1991).
RN [40]
RP VARIANT EDINBURGH GLY-52, AND NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1551676; DOI=10.1007/BF02265300;
RA Lightfoot T., Joshi R., Nuki G., Snyder F.F.;
RT "The point mutation of hypoxanthine-guanine phosphoribosyltransferase
RT (HPRTEdinburgh) and detection by allele-specific polymerase chain
RT reaction.";
RL Hum. Genet. 88:695-696(1992).
RN [41]
RP VARIANTS, AND NUCLEOTIDE SEQUENCE [MRNA] OF 35-50.
RX PubMed=1301916; DOI=10.1093/hmg/1.6.427;
RA Sege-Paterson K., Chambers J., Page T., Jones O.W., Nyhan W.L.;
RT "Characterization of mutations in phenotypic variants of hypoxanthine
RT phosphoribosyltransferase deficiency.";
RL Hum. Mol. Genet. 1:427-432(1992).
RN [42]
RP VARIANT GOUT-HPRT MOOSE JAW GLU-194, AND NUCLEOTIDE SEQUENCE.
RA Lightfoot T., Snyder F.F.;
RL Submitted (MAR-1994) to the EMBL/GenBank/DDBJ databases.
RN [43]
RP VARIANT LNS ISAR PHE-42.
RX PubMed=7627191; DOI=10.1002/humu.1380050413;
RA Burgemeister R., Roetzer E., Gutensohn W., Gehrke M., Schiel W.;
RT "Identification of a new missense mutation in exon 2 of the human
RT hypoxanthine phosphoribosyltransferase gene (HPRTIsar): a further
RT example of clinical heterogeneity in HPRT deficiencies.";
RL Hum. Mutat. 5:341-344(1995).
RN [44]
RP VARIANT ARG-61.
RX PubMed=9003484; DOI=10.1007/s004390050300;
RA Fujimori S., Sakuma R., Yamaoka N., Hakoda M., Yamanaka H.,
RA Kamatani N.;
RT "An asymptomatic germline missense base substitution in the
RT hypoxanthine phosphoribosyltransferase (HPRT) gene that reduces the
RT amount of enzyme in humans.";
RL Hum. Genet. 99:8-10(1997).
RN [45]
RP VARIANT LNS ROANNE VAL-177.
RX PubMed=9452051;
RA Liu G., Aral B., Zabot M.-T., Kamoun P., Ceballos-Picot I.;
RT "The molecular basis of hypoxanthine-guanine phosphoribosyltransferase
RT deficiency in French families; report of two novel mutations.";
RL Hum. Mutat. Suppl. 1:S88-S90(1998).
CC -!- FUNCTION: Converts guanine to guanosine monophosphate, and
CC hypoxanthine to inosine monophosphate. Transfers the 5-
CC phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the
CC purine. Plays a central role in the generation of purine
CC nucleotides through the purine salvage pathway.
CC -!- CATALYTIC ACTIVITY: IMP + diphosphate = hypoxanthine + 5-phospho-
CC alpha-D-ribose 1-diphosphate.
CC -!- CATALYTIC ACTIVITY: GMP + diphosphate = guanine + 5-phospho-alpha-
CC D-ribose 1-diphosphate.
CC -!- COFACTOR: Binds 2 magnesium ions per subunit. The magnesium ions
CC are essentially bound to the substrate and have few direct
CC interactions with the protein.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5.4 uM for IMP;
CC KM=0.45 uM for hypoxanthine;
CC KM=25 uM for pyrophosphate;
CC KM=31 uM for phosphoribosylpyrophosphate;
CC -!- PATHWAY: Purine metabolism; IMP biosynthesis via salvage pathway;
CC IMP from hypoxanthine: step 1/1.
CC -!- SUBUNIT: Homotetramer.
CC -!- INTERACTION:
CC Q96HA8:WDYHV1; NbExp=3; IntAct=EBI-748210, EBI-741158;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- DISEASE: Lesch-Nyhan syndrome (LNS) [MIM:300322]: Characterized by
CC complete lack of enzymatic activity that results in hyperuricemia,
CC choreoathetosis, mental retardation, and compulsive self-
CC mutilation. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Gout HPRT-related (GOUT-HPRT) [MIM:300323]: Characterized
CC by partial enzyme activity and hyperuricemia. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the purine/pyrimidine
CC phosphoribosyltransferase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HPRT1";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/hprt1/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hypoxanthine-guanine
CC phosphoribosyltransferase entry;
CC URL="http://en.wikipedia.org/wiki/Hypoxanthine-guanine_phosphoribosyltransferase";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
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DR EMBL; M31642; AAA52690.1; -; mRNA.
DR EMBL; M26434; AAA36012.1; -; Genomic_DNA.
DR EMBL; AK313435; BAG36226.1; -; mRNA.
DR EMBL; BT019350; AAV38157.1; -; mRNA.
DR EMBL; AY780550; AAV31777.1; -; Genomic_DNA.
DR EMBL; AC004383; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471107; EAX11761.1; -; Genomic_DNA.
DR EMBL; BC000578; AAH00578.1; -; mRNA.
DR EMBL; M12452; AAA52691.1; -; Genomic_DNA.
DR EMBL; S79313; AAB21289.1; -; Genomic_DNA.
DR EMBL; L29383; AAB59391.1; -; mRNA.
DR EMBL; L29382; AAB59392.1; -; mRNA.
DR EMBL; S60300; AAC60591.2; -; mRNA.
DR PIR; A32728; RTHUG.
DR RefSeq; NP_000185.1; NM_000194.2.
DR UniGene; Hs.412707; -.
DR PDB; 1BZY; X-ray; 2.00 A; A/B/C/D=2-218.
DR PDB; 1D6N; X-ray; 2.70 A; A/B=5-218.
DR PDB; 1HMP; X-ray; 2.50 A; A/B=2-218.
DR PDB; 1Z7G; X-ray; 1.90 A; A/B/C/D=2-217.
DR PDB; 2VFA; X-ray; 2.80 A; A/B=49-160.
DR PDB; 3GEP; X-ray; 2.60 A; A/B=2-218.
DR PDB; 3GGC; X-ray; 2.78 A; A/B=2-218.
DR PDB; 3GGJ; X-ray; 2.60 A; A/B=2-218.
DR PDB; 4IJQ; X-ray; 2.00 A; A/B/C/D=2-218.
DR PDB; 4KN6; X-ray; 2.73 A; A=3-218.
DR PDBsum; 1BZY; -.
DR PDBsum; 1D6N; -.
DR PDBsum; 1HMP; -.
DR PDBsum; 1Z7G; -.
DR PDBsum; 2VFA; -.
DR PDBsum; 3GEP; -.
DR PDBsum; 3GGC; -.
DR PDBsum; 3GGJ; -.
DR PDBsum; 4IJQ; -.
DR PDBsum; 4KN6; -.
DR ProteinModelPortal; P00492; -.
DR SMR; P00492; 5-218.
DR IntAct; P00492; 4.
DR MINT; MINT-1443310; -.
DR STRING; 9606.ENSP00000298556; -.
DR BindingDB; P00492; -.
DR ChEMBL; CHEMBL2360; -.
DR DrugBank; DB01033; Mercaptopurine.
DR DrugBank; DB00352; Thioguanine.
DR PhosphoSite; P00492; -.
DR DMDM; 123497; -.
DR OGP; P00492; -.
DR REPRODUCTION-2DPAGE; IPI00218493; -.
DR PaxDb; P00492; -.
DR PeptideAtlas; P00492; -.
DR PRIDE; P00492; -.
DR DNASU; 3251; -.
DR Ensembl; ENST00000298556; ENSP00000298556; ENSG00000165704.
DR GeneID; 3251; -.
DR KEGG; hsa:3251; -.
DR UCSC; uc004exl.4; human.
DR CTD; 3251; -.
DR GeneCards; GC0XP133594; -.
DR HGNC; HGNC:5157; HPRT1.
DR HPA; CAB012200; -.
DR HPA; HPA006360; -.
DR MIM; 300322; phenotype.
DR MIM; 300323; phenotype.
DR MIM; 308000; gene.
DR neXtProt; NX_P00492; -.
DR Orphanet; 79233; Kelley-Seegmiller syndrome.
DR Orphanet; 510; Lesch-Nyhan syndrome.
DR PharmGKB; PA29427; -.
DR eggNOG; COG0634; -.
DR HOGENOM; HOG000236521; -.
DR HOVERGEN; HBG000242; -.
DR KO; K00760; -.
DR OMA; LIMDSRT; -.
DR OrthoDB; EOG7673CK; -.
DR PhylomeDB; P00492; -.
DR BioCyc; MetaCyc:HS09275-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P00492; -.
DR UniPathway; UPA00591; UER00648.
DR ChiTaRS; HPRT1; human.
DR EvolutionaryTrace; P00492; -.
DR GeneWiki; Hypoxanthine-guanine_phosphoribosyltransferase; -.
DR GenomeRNAi; 3251; -.
DR NextBio; 12927; -.
DR PRO; PR:P00492; -.
DR Bgee; P00492; -.
DR CleanEx; HS_HPRT1; -.
DR Genevestigator; P00492; -.
DR GO; GO:0005829; C:cytosol; IBA:RefGenome.
DR GO; GO:0052657; F:guanine phosphoribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0004422; F:hypoxanthine phosphoribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0006168; P:adenine salvage; IBA:RefGenome.
DR GO; GO:0007610; P:behavior; IMP:UniProtKB.
DR GO; GO:0021954; P:central nervous system neuron development; IEA:Ensembl.
DR GO; GO:0021895; P:cerebral cortex neuron differentiation; IEA:Ensembl.
DR GO; GO:0019835; P:cytolysis; IEA:Ensembl.
DR GO; GO:0048813; P:dendrite morphogenesis; IEA:Ensembl.
DR GO; GO:0042417; P:dopamine metabolic process; IEA:Ensembl.
DR GO; GO:0046038; P:GMP catabolic process; IDA:UniProtKB.
DR GO; GO:0032263; P:GMP salvage; IBA:RefGenome.
DR GO; GO:0007625; P:grooming behavior; IEA:Ensembl.
DR GO; GO:0006178; P:guanine salvage; IDA:UniProtKB.
DR GO; GO:0043103; P:hypoxanthine salvage; IDA:UniProtKB.
DR GO; GO:0032264; P:IMP salvage; IBA:RefGenome.
DR GO; GO:0046651; P:lymphocyte proliferation; IEA:Ensembl.
DR GO; GO:0045964; P:positive regulation of dopamine metabolic process; IMP:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
DR GO; GO:0006166; P:purine ribonucleoside salvage; IMP:UniProtKB.
DR GO; GO:0001975; P:response to amphetamine; IEA:Ensembl.
DR GO; GO:0021756; P:striatum development; IEA:Ensembl.
DR InterPro; IPR005904; Hxn_phspho_trans.
DR InterPro; IPR000836; PRibTrfase_dom.
DR Pfam; PF00156; Pribosyltran; 1.
DR TIGRFAMs; TIGR01203; HGPRTase; 1.
DR PROSITE; PS00103; PUR_PYR_PR_TRANSFER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Glycosyltransferase;
KW Gout; Magnesium; Metal-binding; Nucleotide-binding; Purine salvage;
KW Reference proteome; Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 218 Hypoxanthine-guanine
FT phosphoribosyltransferase.
FT /FTId=PRO_0000139585.
FT NP_BIND 134 142 GMP.
FT NP_BIND 186 188 GMP.
FT ACT_SITE 138 138 Proton acceptor (Probable).
FT METAL 194 194 Magnesium.
FT BINDING 69 69 GMP.
FT BINDING 166 166 GMP.
FT BINDING 194 194 GMP; via carbonyl oxygen.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 7 7 G -> D (in GOUT-HPRT; Gravesend).
FT /FTId=VAR_006750.
FT VARIANT 8 8 V -> G (in LNS; HB).
FT /FTId=VAR_006751.
FT VARIANT 16 16 G -> D (in LNS; FG).
FT /FTId=VAR_006752.
FT VARIANT 16 16 G -> S (in GOUT-HPRT; Urangan).
FT /FTId=VAR_006753.
FT VARIANT 20 20 D -> V (in GOUT-HPRT; Mashad).
FT /FTId=VAR_006754.
FT VARIANT 23 23 C -> W (in GOUT-HPRT; JS).
FT /FTId=VAR_006755.
FT VARIANT 28 28 Missing (in LNS).
FT /FTId=VAR_012312.
FT VARIANT 41 41 L -> P (in LNS; Detroit).
FT /FTId=VAR_006756.
FT VARIANT 42 42 I -> F (in LNS; Isar).
FT /FTId=VAR_006757.
FT VARIANT 42 42 I -> T (in LNS; Heapey).
FT /FTId=VAR_006758.
FT VARIANT 43 44 MD -> RN (in LNS; Salamanca).
FT /FTId=VAR_006759.
FT VARIANT 45 45 R -> K (in LNS; RJK 2163).
FT /FTId=VAR_006760.
FT VARIANT 48 48 R -> H (in GOUT-HPRT; AD and DD).
FT /FTId=VAR_006761.
FT VARIANT 50 50 A -> P (in LNS; LW).
FT /FTId=VAR_006763.
FT VARIANT 50 50 A -> V (in LNS; 1265).
FT /FTId=VAR_006762.
FT VARIANT 51 51 R -> G (in GOUT-HPRT; Toronto).
FT /FTId=VAR_006764.
FT VARIANT 51 51 R -> P (in LNS; Banbury).
FT /FTId=VAR_006765.
FT VARIANT 52 52 D -> G (in Edinburgh).
FT /FTId=VAR_006766.
FT VARIANT 53 53 V -> A (in GOUT-HPRT; MG).
FT /FTId=VAR_006767.
FT VARIANT 53 53 V -> M (in GOUT-HPRT; TE).
FT /FTId=VAR_006768.
FT VARIANT 54 54 M -> L (in LNS; Japan-1).
FT /FTId=VAR_006769.
FT VARIANT 57 57 M -> T (in LNS; Montreal).
FT /FTId=VAR_006770.
FT VARIANT 58 58 G -> R (in GOUT-HPRT; Toowong).
FT /FTId=VAR_006771.
FT VARIANT 61 61 H -> R (enzyme activity 37% of normal;
FT asymptomatic).
FT /FTId=VAR_006772.
FT VARIANT 70 70 G -> E (in LNS; New Haven/1510).
FT /FTId=VAR_006773.
FT VARIANT 71 71 G -> R (in LNS; Yale).
FT /FTId=VAR_006774.
FT VARIANT 74 74 F -> L (in LNS; Flint/RJK 892/DW/Perth/
FT 1522).
FT /FTId=VAR_006775.
FT VARIANT 78 78 L -> V (in GOUT-HPRT; Swan).
FT /FTId=VAR_006776.
FT VARIANT 80 80 D -> V (in GOUT-HPRT; Arlington).
FT /FTId=VAR_006777.
FT VARIANT 104 104 S -> R (in GOUT-HPRT; Munich).
FT /FTId=VAR_006778.
FT VARIANT 110 110 S -> L (in GOUT-HPRT; London).
FT /FTId=VAR_006779.
FT VARIANT 130 130 V -> D (in LNS; Midland/RJK 896).
FT /FTId=VAR_006780.
FT VARIANT 131 131 L -> S (in LNS; RJK 1784).
FT /FTId=VAR_006781.
FT VARIANT 132 132 I -> M (in GOUT-HPRT; Ann-Arbor).
FT /FTId=VAR_006782.
FT VARIANT 132 132 I -> T (in LNS; Runcorn).
FT /FTId=VAR_006783.
FT VARIANT 135 135 D -> G (in GOUT-HPRT; Yeronga).
FT /FTId=VAR_006784.
FT VARIANT 143 143 M -> K (in LNS; RJK 1210).
FT /FTId=VAR_006785.
FT VARIANT 143 143 M -> MA (in LNS; RW).
FT /FTId=VAR_006786.
FT VARIANT 161 161 A -> S (in GOUT-HPRT; Milwaukee/RJK 949).
FT /FTId=VAR_006787.
FT VARIANT 162 162 S -> R (in LNS; Farnham).
FT /FTId=VAR_006788.
FT VARIANT 168 168 T -> I (in GOUT-HPRT; Brisbane).
FT /FTId=VAR_006789.
FT VARIANT 176 176 P -> L (in LNS; Marlow).
FT /FTId=VAR_006790.
FT VARIANT 177 177 D -> V (in LNS; Roanne).
FT /FTId=VAR_006791.
FT VARIANT 177 177 D -> Y (in LNS; RJK 2185).
FT /FTId=VAR_006792.
FT VARIANT 179 180 VG -> GR (in GOUT-HPRT; Japan-2).
FT /FTId=VAR_006794.
FT VARIANT 179 179 Missing (in LNS; Michigan).
FT /FTId=VAR_006793.
FT VARIANT 183 183 I -> T (in GOUT-HPRT; JF).
FT /FTId=VAR_006796.
FT VARIANT 188 188 V -> A (in Japan).
FT /FTId=VAR_006795.
FT VARIANT 194 194 D -> E (in GOUT-HPRT; Moose-Jaw; results
FT in cooperativity and decreased substrate
FT affinities).
FT /FTId=VAR_006797.
FT VARIANT 194 194 D -> N (in LNS; Kinston/RJK 2188).
FT /FTId=VAR_006798.
FT VARIANT 195 195 Y -> C (in GOUT-HPRT; Dirranbandi).
FT /FTId=VAR_006799.
FT VARIANT 199 199 F -> V (in LNS; New Briton/RJK 950).
FT /FTId=VAR_006800.
FT VARIANT 201 201 D -> G (in GOUT-HPRT; Ashville).
FT /FTId=VAR_006801.
FT VARIANT 201 201 D -> N (in GOUT-HPRT; RB).
FT /FTId=VAR_006802.
FT VARIANT 201 201 D -> Y (in LNS; GM).
FT /FTId=VAR_006803.
FT VARIANT 204 204 H -> D (in LNS; RJK 1874).
FT /FTId=VAR_006804.
FT VARIANT 204 204 H -> R (in LNS; 779).
FT /FTId=VAR_006805.
FT VARIANT 206 206 C -> Y (in LNS; Reading/RJK 1727).
FT /FTId=VAR_006806.
FT MUTAGEN 69 69 K->A: Reduced affinity for hypoxanthine,
FT phosphoribosylpyrophosphate and IMP.
FT Reduced catalytic activity.
FT STRAND 7 9
FT STRAND 12 14
FT HELIX 19 21
FT HELIX 26 28
FT TURN 29 31
FT STRAND 32 37
FT HELIX 39 57
FT STRAND 62 67
FT TURN 69 71
FT HELIX 73 86
FT STRAND 88 90
FT STRAND 95 100
FT STRAND 109 118
FT HELIX 122 125
FT STRAND 128 136
FT HELIX 140 151
FT STRAND 156 166
FT STRAND 177 183
FT STRAND 188 190
FT STRAND 195 197
FT STRAND 198 201
FT STRAND 204 208
FT HELIX 210 216
SQ SEQUENCE 218 AA; 24579 MW; 1928EE69517CCB40 CRC64;
MATRSPGVVI SDDEPGYDLD LFCIPNHYAE DLERVFIPHG LIMDRTERLA RDVMKEMGGH
HIVALCVLKG GYKFFADLLD YIKALNRNSD RSIPMTVDFI RLKSYCNDQS TGDIKVIGGD
DLSTLTGKNV LIVEDIIDTG KTMQTLLSLV RQYNPKMVKV ASLLVKRTPR SVGYKPDFVG
FEIPDKFVVG YALDYNEYFR DLNHVCVISE TGKAKYKA
//

MIM 300322
*RECORD*
*FIELD* NO
300322
*FIELD* TI
#300322 LESCH-NYHAN SYNDROME; LNS
;;HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1 DEFICIENCY;;
read moreHPRT1 DEFICIENCY;;
HPRT DEFICIENCY;;
HPRT DEFICIENCY, COMPLETE
HPRT DEFICIENCY, NEUROLOGIC VARIANT, INCLUDED;;
LESCH-NYHAN SYNDROME, NEUROLOGIC VARIANT, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Lesch-Nyhan syndrome
is caused by mutation in the HPRT gene (308000) encoding hypoxanthine
guanine phosphoribosyltransferase.

CLINICAL FEATURES

The features of the Lesch-Nyhan syndrome are mental retardation, spastic
cerebral palsy, choreoathetosis, uric acid urinary stones, and
self-destructive biting of fingers and lips. Megaloblastic anemia has
been found by some (van der Zee et al., 1968).

Virtually complete deficiency of HPRT residual activity (less than 1.5%)
is associated with the Lesch-Nyhan syndrome, whereas partial deficiency
(at least 8%) is associated with the Kelley-Seegmiller syndrome
(300323). LNS is characterized by abnormal metabolic and neurologic
manifestations. In contrast, Kelley-Seegmiller syndrome is usually
associated only with the clinical manifestations of excessive purine
production. Renal stones, uric acid nephropathy, and renal obstruction
are often the presenting symptoms of Kelley-Seegmiller syndrome, but
rarely of LNS. After puberty, the hyperuricemia in Kelley-Seegmiller
syndrome may cause gout. A third group of patients, with 1.5 to 8% of
HPRT activity, is associated with a neurologic variant of LNS, with uric
acid overproduction and neurologic disability that varies from minor
clumsiness to debilitating extrapyramidal and pyramidal motor
dysfunction (Jinnah and Friedmann, 2001).

Bakay et al. (1979) restudied a patient with HPRT deficiency,
choreoathetosis, spasticity, dysarthria, and hyperuricemia, but normal
intelligence and no self-mutilation. (A maternal uncle had been
identically affected.) Although HPRT deficiency seemed to be complete,
cultured fibroblasts had some capacity for metabolism of hypoxanthine
and guanine. Page et al. (1987) described 2 brothers and 2 of their
maternal uncles who had HPRT deficiency as the cause of mild mental
retardation, spastic gait, and pyramidal tract sign. They were,
furthermore, short of stature with proximally placed thumbs and fifth
finger clinodactyly. Activity of the enzyme was virtually zero in
lysates of red cells or hair roots, but in intact fibroblasts the level
of activity was 7.5% of normal. Kinetic studies also demonstrated
differences. A sister of the brothers was, by enzyme assay,
heterozygous. One of the affected uncles had advanced tophaceous gout by
age 32 years.

- Clinical Variability

Hladnik et al. (2008) reported a family in which 5 individuals carrying
the same splice site mutation in the HPRT gene showed marked phenotypic
variability resulting from HPRT deficiency. One patient had classic
Lesch-Nyhan syndrome with delayed development, spasticity, dystonia, and
self-injurious behavior. Two patients had an intermediate phenotype with
mild cognitive and learning difficulties, dystonia, and increased uric
acid, but no self-injurious behavior, and 2 had mild spasticity, gout,
and normal IQ. Hladnik et al. (2008) postulated that each individual had
various expression of the mutant and wildtype transcript, and emphasized
that individuals with the same genotype may not necessarily have the
identical phenotype.

Sarafoglou et al. (2010) reported a 3-generation family in which 3
individuals carrying the same missense mutation in the HPRT1 gene showed
phenotypic variability. The proband presented at age 14.5 months with
increased uric acid levels and later showed mildly delayed development.
His cousin was diagnosed at age 26 months, and had mild generalized
hypotonia, delayed motor development, focal dystonia of the lower limbs,
and mild developmental impairment with speech delay. The boys'
65-year-old grandfather was more severely affected, with borderline
cognitive function, severe dyslexia, spasticity, and flexion
contractures leading to motor impairment. He had a long history of gout,
nephrolithiasis, and progressive renal dysfunction. Medical history
revealed that his symptoms had been attributed to cerebral palsy due to
perinatal asphyxia. Enzymatic studies of cultured fibroblasts showed
decreased activity in the proband, more severely decreased activity in
the cousin, and the most severely decreased activity in the grandfather,
consistent with their phenotypes. Cells from the grandfather grew more
slowly than those from the grandchildren and appeared less robust.

BIOCHEMICAL FEATURES

A 200-fold increase in the conversion of C(14)-labeled glycine to uric
acid was observed by Nyhan et al. (1965). Seegmiller et al. (1967)
demonstrated deficiency in the enzyme hypoxanthine-guanine
phosphoribosyltransferase (HPRT). That the enzyme deficiency resulted in
excessive purine synthesis suggested that the enzyme (or the product of
its function) normally plays a controlling role in purine metabolism.
Resistance to 8-azaguanine in cultured diploid human fibroblasts was
induced by x-ray in pioneer experiments (Albertini and DeMars, 1973).
Mutation in the HPRT gene is the basis for this resistance. Lesch-Nyhan
cells are resistant to 8-azaguanine. Upchurch et al. (1975) found a
normal amount of cross-reacting material in 1 of 12 patients with HPRT
deficiency. The others had less than 3% of the normal amount. Ghangas
and Milman (1975) confirmed this by another method. Wilson et al. (1986)
analyzed cell lines of 24 patients with HPRT deficiency at the levels of
residual protein, mRNA, and DNA. At least 16 patients had unique
mutations of the HPRT gene. Most cell lines had normal quantities of
mRNA but undetectable quantities of enzyme. Eight of the patients
retained significant quantities of structurally altered but functionally
abnormal HPRT enzyme variants. A minority of patients lacked both enzyme
and mRNA.

INHERITANCE

X-linkage was first suggested by Hoefnagel et al. (1965) and was
supported by a rapidly accumulated series of families with deficiency of
HPRT. Rosenbloom et al. (1967) and Migeon et al. (1968) demonstrated 2
populations of fibroblasts, as regards the relevant enzyme activity, in
heterozygous females, thus providing support both for X-linkage and for
the Lyon hypothesis. Studies using human-mouse somatic cell hybrids
indicate, by reasoning similar to that used for locating the thymidine
kinase locus to chromosome 17 (188300), that the HPRT locus is on the X
chromosome (Nabholz et al., 1969). Mosaicism can be demonstrated by
study of hair roots in women heterozygous for the Lesch-Nyhan syndrome
(Silvers et al., 1972). Francke et al. (1976) studied the frequency of
new mutations among affected males. The Lesch-Nyhan syndrome is
particularly favorable for this purpose because no affected males
reproduce, the diagnosis is unequivocal and cases come readily to
attention, and particularly because heterozygosity can be demonstrated
in females by the existence of 2 populations of cultured fibroblasts.
There were few new mutations, contrary to the expected one-third. On the
other hand, about one-half of heterozygous females were new mutations,
as is predicted by theory. The finding may indicate a higher frequency
of mutation in males than in females. Another possibility is the role of
somatic and half-chromatid mutations (Gartler and Francke, 1975). New
mutation cases of heterozygous females had elevated parental age. Vogel
(1977) reviewed the evidence concerning hemophilia and the Lesch-Nyhan
syndrome leading to the conclusion that the mutation rate is higher in
males than in females. Evidence that the mutation rate for the
Lesch-Nyhan disease may be higher in males than in females was reviewed
by Francke et al. (1976) and criticized by Morton and Lalouel (1977).
Francke et al. (1977) answered the criticism. Strauss et al. (1980)
showed that females heterozygous for the Lesch-Nyhan mutation have 2
populations of peripheral blood lymphocytes with regard to sensitivity
to 6-thioguanine inhibition of tritiated thymidine incorporation
following phytohemagglutinin stimulation. Henderson et al. (1969)
concluded that the locus for HPRT is closely linked to the Xg (314700)
locus; Greene et al. (1970) concluded, however, that the HPRT and Xg
loci 'are sufficient distance from each other on the human X chromosome
that linkage cannot be detected.' Nyhan et al. (1970) observed a sibship
in which both HPRT deficiency and G6PD deficiency (300908) were
segregating and found 2 of 4 recombinants. Nyhan et al. (1970) also
found that heterozygotes had normal levels of HPRT in red cells. They
interpreted this as indicating a selective advantage of G6PD-normal over
G6PD-deficient cells. (In adrenoleukodystrophy (300100), it is the
mutant cell that enjoys the selective advantage.)

Yukawa et al. (1992) described a seemingly typical case of Lesch-Nyhan
syndrome in a female with a normal karyotype. The parents were
nonconsanguineous. In addition to unusual lyonization, uniparental
disomy is a possible explanation.

PATHOGENESIS

- Pathogenesis of Mental Retardation and Self-injurious Behavior

Wong et al. (1996) discussed 3 lines of evidence that had suggested that
HPRT deficiency is associated with abnormal dopamine (DA) function in
LNS: (1) an autopsy study of 3 LNS subjects demonstrated a marked
reduction in the DA content and in the activity of DNA-synthesizing
enzymes in the caudate and putamen (Lloyd et al., 1981); (2) when
neonatal rats are depleted of DA with the neurotoxin 6-hydroxydopamine,
self-injurious behavior, similar to that seen in LNS, occurred when the
rats were challenged with 3,4-dihydroxyphenylalanine (L-dopa) as adults
(Breese et al., 1990); and (3) in an HPRT-deficient mutant mouse strain,
there is a reduction of striatal tyrosine hydroxylase and in the number
of striatal dopamine transporters (Jinnah et al., 1994). To establish
that DA deficiency is present in LNS, Wong et al. (1996) used a ligand
that binds to DA transporters to estimate the density of DA-containing
neurons in the caudate and putamen of 6 subjects with classic LNS. They
made comparisons with 10 control subjects and 3 patients with Rett
syndrome (312750). Depending on the method of analysis, a 50 to 63%
reduction of the binding to DA transporters in the caudate and a 64 to
75% reduction in the putamen of LNS patients was observed compared to
the normal control group; similar reductions were found between Rett
syndrome and LNS patients. Volumetric magnetic resonance imaging studies
detected a 30% reduction in the caudate volume of LNS patients. To
ensure that a reduction in the caudate volume would not confound the
results, Wong et al. (1996) performed a rigorous partial volume
correction of the caudate time activity curve. This correction resulted
in an even greater decrease in the caudate-cerebellar ratio in LNS
patients when contrasted to controls.

Ernst et al. (1996) concluded that patients with Lesch-Nyhan disease
have abnormally few dopaminergic nerve terminals and cell bodies. The
abnormality involves all dopaminergic pathways and is not restricted to
the basal ganglia. These dopaminergic deficits are pervasive and appear
to be developmental in origin, which suggested that they contribute to
the characteristic neuropsychiatric manifestations of the disease. These
studies were done with positron-emission tomography (PET) with the
tracer fluorodopa-F18. This tracer, an analog of dopa, is a large,
neutral amino acid that is transported into presynaptic neurons, where
it is converted by the enzyme dopa decarboxylase (107930) into
fluorodopamine F18, which subsequently enters catecholamine-storage
vesicles. Hence, data obtained with the use of fluorodopa-F18 and PET
reflect dopa decarboxylase activity and dopamine-storage processes. In
an accompanying editorial, Nyhan and Wong (1996) commented on the new
findings and reviewed the normal function of HPRT with a diagram.

Ceballos-Picot et al. (2009) demonstrated that HPRT deficiency
influences early developmental processes controlling the dopaminergic
phenotype. Microarray methods and quantitative PCR were applied to 10
different HPRT-deficient sublines derived from the hybrid MN9D cell
line, derived from somatic fusion of embryonic mouse primary midbrain
dopaminergic neurons with a mouse neuroblastoma line. There were
consistent increases in mRNAs for engrailed-1 (EN1; 131290) and -2 (EN2;
131310), transcription factors known to play a role in the specification
and survival of dopamine neurons. The increases in mRNAs were
accompanied by increases in engrailed proteins, and restoration of HPRT
reverted engrailed expression towards normal levels. The functional
relevance of the abnormal developmental molecular signature of the
HPRT-deficient MN9D cells was evident in impoverished neurite outgrowth
when the cells were forced to differentiate chemically. These
abnormalities were also seen in HPRT-deficient sublines from the
SK-N-BE(2)-M17 human neuroblastoma line, and overexpression of engrailed
was documented in primary fibroblasts from patients with Lesch-Nyhan
disease. Ceballos-Picot et al. (2009) concluded that HPRT deficiency may
affect dopaminergic neurons by influencing early developmental
mechanisms.

Cristini et al. (2010) examined the effect of HPRT deficiency on the
differentiation of neurons in human neural stem cells (NSCs) isolated
from human Lesch-Nyhan disease fetal brain. LNS NSCs demonstrated
aberrant expression of several transcription factors and DA markers, and
HPRT-deficient dopaminergic neurons demonstrated a striking deficit in
neurite outgrowth. Exposure of the LNS NSCs to retinoic acid medium
elicited the generation of dopaminergic neurons. The authors concluded
that neurogenesis is aberrant in LNS NSCs and suggested a role for HPRT
in neurodevelopment.

DIAGNOSIS

- Prenatal Diagnosis

Fujimoto et al. (1968) presented evidence that the disease can be
recognized in the fetus well before 20 weeks, i.e., within the limit for
elective abortion. The method used was an autoradiographic test for HPRT
activity, applied to cells obtained by amniocentesis. Boyle et al.
(1970) made the prenatal diagnosis and performed therapeutic abortion.
Gibbs et al. (1984) showed that by ultramicroassay of HPRT it is
possible to diagnose the Lesch-Nyhan syndrome on the basis of chorionic
villi sampled at 8-9 weeks of gestation.

Graham et al. (1996) investigated 15 pregnancies at risk for Lesch-Nyhan
syndrome between 8 and 17 weeks' gestation by measurement of HPRT and
APRT (102600) enzyme activities in chorionic villus samples (cultured
and uncultured) or in cultured amniotic fluid cells. Ten pregnancies had
normal enzyme levels and a normal outcome, while a further 2 predicted
to be normal miscarried later in the pregnancy. Three pregnancies had
low levels of residual HPRT activity in chorionic villi. Comparable
levels of residual activity in the index case in 2 pregnancies and in
cells from the abortus in the third case confirmed that the pregnancies
were indeed affected.

MOLECULAR GENETICS

For a discussion of the molecular defects involved in Lesch-Nyhan
syndrome, see the HPRT1 gene (308000).

GENOTYPE/PHENOTYPE CORRELATIONS

There is variable disease severity in patients with Lesch-Nyhan
syndrome, with an inverse relationship between HPRT1 enzyme activity
measured in intact cells and clinical severity. Patients with classic
Lesch-Nyhan disease, the most severe and frequent form, have the lowest
HPRT enzyme activity (less than 1.5% of normal) in intact cultured
fibroblasts. Patients with partial HPRT deficiency, designated as
Lesch-Nyhan variants, have HPRT1 enzyme activity ranging from 1.5 to
8.0%. Individuals with an intermediate variant form known as the
'neurologic variant' are neurologically indistinguishable from patients
with Lesch-Nyhan disease, but they do not have self-injurious behaviors
and intelligence is normal or near-normal. The least-affected patients
with the variant form have residual HPRT1 enzyme activity exceeding 8%;
their only manifestations are attributed to hyperuricemia, and include
gout, hematuria, and nephrolithiasis (summary by Sarafoglou et al.,
2010).

HISTORY

Lesch and Nyhan (1964) described the disorder that bears their names on
the basis of 2 brothers. Nyhan (1997) gave an account of the recognition
of the syndrome as an inborn error of purine metabolism.

Preston (2007) provided a popular description of the discovery of the
disorder and what the study of a rare disorder such as this can tell us
about human behavior.

*FIELD* SA
Rosenbloom et al. (1967)
*FIELD* RF
1. Albertini, R. J.; DeMars, R.: Somatic cell mutation: detection
and quantification of x-ray-induced mutation in cultured, diploid
human fibroblasts. Mutat. Res. 18: 199-224, 1973.

2. Bakay, B.; Nissinen, E.; Sweetman, L.; Francke, U.; Nyhan, W. L.
: Utilization of purines by an HPRT variant in an intelligent, nonmutilative
patient with features of the Lesch-Nyhan syndrome. Pediat. Res. 13:
1365-1370, 1979.

3. Boyle, J. A.; Raivio, K. O.; Astrin, K. H.; Shulman, J. D.; Graf,
M. L.; Seegmiller, J. E.; Jacobson, C. B.: Lesch-Nyhan syndrome:
preventive control by prenatal diagnosis. Science 169: 688-689,
1970.

4. Breese, G. R.; Criswell, H. E.; Duncan, G. E.; Mueller, R. A.:
A dopamine deficiency model of Lesch-Nyhan disease: the neonatal-6-OHDA-lesioned
rat. Brain Res. Bull. 25: 447-484, 1990.

5. Ceballos-Picot, I.; Mockel, L.; Potier, M.-C.; Dauphinot, L.; Shirley,
T. L.; Torero-Ibad, R.; Fuchs, J.; Jinnah, H. A.: Hypoxanthine-guanine
phosphoribosyl transferase regulates early developmental programming
of dopamine neurons: implications for Lesch-Nyhan disease pathogenesis. Hum.
Molec. Genet. 18: 2317-2327, 2009.

6. Cristini, S.; Navone, S.; Canzi, L.; Acerbi, F.; Ciusani, E.; Hladnik,
U.; de Gemmis, P.; Alessandri, G.; Colombo, A.; Parati, E.; Invernici,
G.: Human neural stem cells: a model system for the study of Lesch-Nyhan
disease neurological aspects. Hum. Molec. Genet. 19: 1939-1950,
2010.

7. Ernst, M.; Zametkin, A. J.; Matochik, J. A.; Pascualvaca, D.; Jons,
P. H.; Hardy, K.; Hankerson, J. G.; Doudet, D. J.; Cohen, R. M.:
Presynaptic dopaminergic deficits in Lesch-Nyhan disease. New Eng.
J. Med. 334: 1568-1572, 1996.

8. Francke, U.; Felsenstein, J.; Gartler, S. M.; Migeon, B. R.; Dancis,
J.; Seegmiller, J. E.; Bakay, B.; Nyhan, W. L.: The occurrence of
new mutants in the X-linked recessive Lesch-Nyhan disease. Am. J.
Hum. Genet. 28: 123-137, 1976.

9. Francke, U.; Felsenstein, J.; Gartler, S. M.; Nyhan, W. L.; Seegmiller,
J. E.: Answer to criticism of Morton and Lalouel. (Letter) Am. J.
Hum. Genet. 29: 307-310, 1977.

10. Fujimoto, W. Y.; Seegmiller, J. E.; Uhlendorf, B. W.; Jacobson,
C. B.: Biochemical diagnosis of X-linked disease in utero. (Letter) Lancet 292:
511-512, 1968. Note: Originally Volume II.

11. Gartler, S. M.; Francke, U.: Half-chromatid mutation: transmission
in humans? Am. J. Hum. Genet. 27: 218-223, 1975.

12. Ghangas, G. S.; Milman, G.: Radioimmune determination of hypoxanthine
phosphoribosyltransferase crossreacting material in erythrocytes of
Lesch-Nyhan patients. Proc. Nat. Acad. Sci. 72: 4147-4150, 1975.

13. Gibbs, R. A.; McFadyen, I. R.; Crawfurd, M. d'A.; de Muinck Keizer,
E. E.; Headhouse-Benson, C. M.; Wilson, T. M.; Farrant, P. H.: First-trimester
diagnosis of Lesch-Nyhan syndrome. Lancet 324: 1180-1183, 1984.
Note: Originally Volume II.

14. Graham, G. W.; Aitken, D. A.; Connor, J. M.: Prenatal diagnosis
by enzyme analysis in 15 pregnancies at risk for the Lesch-Nyhan syndrome. Prenatal
Diag. 16: 647-651, 1996.

15. Greene, M. L.; Nyhan, W. L.; Seegmiller, J. E.: Hypoxanthine-guanine
phosphoribosyltransferase deficiency and Xg blood group. Am. J. Hum.
Genet. 22: 50-54, 1970.

16. Henderson, J. F.; Kelley, W. N.; Rosenbloom, F. M.; Seegmiller,
J. E.: Inheritance of purine phosphoribosyltransferases in man. Am.
J. Hum. Genet. 21: 61-70, 1969.

17. Hladnik, U.; Nyhan, W. L.; Bertelli, M.: Variable expression
of HPRT deficiency in 5 members of a family with the same mutation. Arch.
Neurol. 65: 1240-1243, 2008.

18. Hoefnagel, D.; Andrew, E. D.; Mireault, N. G.; Berndt, W. O.:
Hereditary choreoathetosis, self-mutilation and hyperuricemia in young
males. New Eng. J. Med. 273: 130-135, 1965.

19. Jinnah, H. A.; Friedmann, T.: Lesch-Nyhan disease and its variants.In:
Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The
Metabolic & Molecular Bases of Inherited Disease. Vol. II. 8th ed.
New York: McGraw-Hill 2001. P. 2537.

20. Jinnah, H. A.; Wojcik, B. E.; Hunt, M.; Narang, N.; Lee, K. Y.;
Goldstein, M.; Wamsley, J. K.; Langlais, P. J.; Friedmann, T.: Dopamine
deficiency in a genetic mouse model of Lesch-Nyhan disease. J. Neurosci. 14:
1164-1174, 1994.

21. Lesch, M.; Nyhan, W. L.: A familial disorder of uric acid metabolism
and central nervous system function. Am. J. Med. 36: 561-570, 1964.

22. Lloyd, K. G.; Hornykiewicz, O.; Davidson, L.; Shannak, K.; Farley,
I.; Goldstein, M.; Shibuya, M.; Kelley, W. N.; Fox, I. H.: Biochemical
evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan
syndrome. New Eng. J. Med. 305: 1106-1111, 1981.

23. Migeon, B. R.; Der Kaloustian, V. M.; Nyhan, W. L.; Young, W.
J.; Childs, B.: X-linked hypoxanthine-guanine phosphoribosyl transferase
deficiency: heterozygote has two clonal populations. Science 160:
425-427, 1968.

24. Morton, N. E.; Lalouel, J. M.: Genetic epidemiology of Lesch-Nyhan
disease. (Letter) Am. J. Hum. Genet. 29: 304-307, 1977.

25. Nabholz, M.; Miggiano, V.; Bodmer, W.: Genetic analysis with
human-mouse somatic cell hybrids. Nature 223: 358-363, 1969.

26. Nyhan, W. L.: The recognition of Lesch-Nyhan syndrome as an inborn
error of purine metabolism. J. Inherit. Metab. Dis. 20: 171-178,
1997.

27. Nyhan, W. L.; Bakay, B.; Connor, J. D.; Marks, J. F.; Keele, D.
K.: Hemizygous expression of glucose-6-phosphate dehydrogenase in
erythrocytes of heterozygotes for the Lesch-Nyhan syndrome. Proc.
Nat. Acad. Sci. 65: 214-218, 1970.

28. Nyhan, W. L.; Olivier, W. J.; Lesch, M.: A familial disorder
of uric acid metabolism and central nervous system function. J. Pediat. 67:
257-263, 1965.

29. Nyhan, W. L.; Wong, D. F.: New approaches to understanding Lesch-Nyhan
disease. (Editorial) New Eng. J. Med. 334: 1602-1604, 1996.

30. Page, T.; Nyhan, W. L.; Morena de Vega, V.: Syndrome of mild
mental retardation, spastic gait, and skeletal malformations in a
family with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase. Pediatrics 79:
713-717, 1987.

31. Preston, R.: An error in the code. New Yorker August 13: 30-36,
2007.

32. Rosenbloom, F. M.; Kelley, W. N.; Henderson, J. F.; Seegmiller,
J. E.: Lyon hypothesis and X-linked disease. (Letter) Lancet 290:
305-306, 1967. Note: Originally Volume II.

33. Rosenbloom, F. M.; Kelley, W. N.; Miller, J.; Henderson, J. F.;
Seegmiller, J. E.: Inherited disorder of purine metabolism: correlation
between central nervous system dysfunction and biochemical defects. JAMA 202:
175-177, 1967.

34. Sarafoglou, K.; Grosse-Redlinger, K.; Boys, C. J.; Charnas, L.;
Otten, N.; Broock, R.; Nyhan, W. L.: Lesch-Nyhan variant syndrome:
variable presentation in 3 affected family members. Arch. Neurol. 67:
761-764, 2010.

35. Seegmiller, J. E.; Rosenbloom, F. M.; Kelley, W. N.: Enzyme defect
associated with a sex-linked human neurological disorder and excessive
purine synthesis. Science 155: 1682-1684, 1967.

36. Silvers, D. N.; Cox, R. P.; Balis, M. E.; Dancis, J.: Detection
of the heterozygote in Lesch-Nyhan disease by hair-root analysis. New
Eng. J. Med. 286: 390-395, 1972.

37. Strauss, G. H.; Allen, E. F.; Albertini, R. J.: An enumerative
assay of purine analogue resistant lymphocytes in women heterozygous
for the Lesch-Nyhan mutation. Biochem. Genet. 18: 529-547, 1980.

38. Upchurch, K. S.; Leyva, A.; Arnold, W. J.; Holmes, E. W.; Kelley,
W. N.: Hypoxanthine phosphoribosyltransferase deficiency: association
of reduced catalytic activity with reduced levels of immunologically
detectable enzyme protein. Proc. Nat. Acad. Sci. 72: 4142-4146,
1975.

39. van der Zee, S. P. M.; Schretlen, E. D. A. M.; Monnens, L. A.
H.: Megaloblastic anaemia in the Lesch-Nyhan syndrome. (Letter) Lancet 291:
1427 only, 1968. Note: Originally Volume I.

40. Vogel, F.: A probable sex difference in some mutation rates.
(Editorial) Am. J. Hum. Genet. 29: 312-319, 1977.

41. Wilson, J. M.; Stout, J. T.; Palella, T. D.; Davidson, B. L.;
Kelley, W. N.; Caskey, C. T.: A molecular survey of hypoxanthine-guanine
phosphoribosyltransferase deficiency in man. J. Clin. Invest. 77:
188-195, 1986.

42. Wong, D. F.; Harris, J. C.; Naidu, S.; Yokoi, F.; Marenco, S.;
Dannals, R. F.; Ravert, H. T.; Yaster, M.; Evans, A.; Rousset, O.;
Bryan, R. N.; Gjedde, A.; Kuhar, M. J.; Breese, G. R.: Dopamine transporters
are markedly reduced in Lesch-Nyhan disease in vivo. Proc. Nat. Acad.
Sci. 93: 5539-5543, 1996.

43. Yukawa, T.; Akazawa, H.; Miyake, Y.; Takahashi, Y.; Nagao, H.;
Takeda, E.: A female patient with Lesch-Nyhan syndrome. Dev. Med.
Child Neurol. 34: 543-546, 1992.

*FIELD* CS
INHERITANCE:
X-linked recessive

GROWTH:
[Height];
Short stature;
[Other];
Growth retardation

ABDOMEN:
[Gastrointestinal];
Vomiting

GENITOURINARY:
[External genitalia, male];
Testicular atrophy;
[Kidneys];
Nephrolithiasis

SKELETAL:
[Feet];
Gout

SKIN, NAILS, HAIR:
[Skin];
Uric acid tophi

NEUROLOGIC:
[Central nervous system];
Motor delay;
Hypotonia;
Self-injurious behavior, median onset age 2 years;
Extrapyramidal signs;
Choreoathetosis;
Dystonia;
Basal ganglia dysfunction;
Spasticity, hyperreflexia;
Opisthotonus;
Dysarthria;
Dysphagia;
Mental retardation (IQ 45-75)

HEMATOLOGY:
Anemia;
Megaloblastic anemia

LABORATORY ABNORMALITIES:
Hyperuricemia;
Hyperuricosuria

MISCELLANEOUS:
Classic Lesch-Nyhan, < 1.5% hypoxanthine phosphoribosyltransferase
(HPRT) activity;
Variant Lesch-Nyhan, 1.5-8% HPRT activity with neurologic abnormalities,
but no self-injurious behavior

MOLECULAR BASIS:
Caused by mutation in the hypoxanthine phosphoribosyltransferase gene
(HPRT1, 308000.0004)

*FIELD* CD
Ada Hamosh: 4/5/2001

*FIELD* ED
joanna: 07/23/2013
joanna: 7/23/2013
joanna: 1/8/2002
joanna: 8/22/2001
joanna: 4/5/2001

*FIELD* CN
George E. Tiller - updated: 8/14/2013
Cassandra L. Kniffin - updated: 7/21/2011
George E. Tiller - updated: 3/30/2010
Cassandra L. Kniffin - updated: 4/6/2009
Victor A. McKusick - updated: 8/10/2007

*FIELD* CD
Ada Hamosh: 4/4/2001

*FIELD* ED
carol: 10/24/2013
carol: 8/16/2013
tpirozzi: 8/15/2013
tpirozzi: 8/14/2013
wwang: 7/26/2011
ckniffin: 7/21/2011
wwang: 3/31/2010
terry: 3/30/2010
terry: 6/3/2009
wwang: 4/13/2009
ckniffin: 4/6/2009
terry: 3/27/2009
carol: 8/10/2007
terry: 8/10/2007
joanna: 4/9/2003
carol: 4/11/2001
mcapotos: 4/6/2001
carol: 4/5/2001
carol: 4/4/2001

MIM 300323
*RECORD*
*FIELD* NO
300323
*FIELD* TI
#300323 KELLEY-SEEGMILLER SYNDROME
;;GOUT, HPRT-RELATED;;
HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1 DEFICIENCY, PARTIAL;;
read moreHPRT DEFICIENCY, PARTIAL;;
HPRT1 DEFICIENCY, PARTIAL
*FIELD* TX
A number sign (#) is used with this entry because Kelley-Seegmiller
syndrome is caused by mutation in the HPRT gene (308000) that results in
partial deficiency of hypoxanthine guanine phosphoribosyltransferase.

DESCRIPTION

Virtually complete deficiency of HPRT residual activity is associated
with the Lesch-Nyhan syndrome (LNS; 300322), whereas partial deficiency
(at least 8%) is associated with the Kelley-Seegmiller syndrome. LNS is
characterized by abnormal metabolic and neurologic manifestations. In
contrast, Kelley-Seegmiller syndrome is usually associated only with the
clinical manifestations of excessive purine production. Renal stones,
uric acid nephropathy, and renal obstruction are often the presenting
symptoms of Kelley-Seegmiller syndrome, but rarely of LNS. After
puberty, the hyperuricemia in Kelley-Seegmiller syndrome may cause gout
(summary by Zoref-Shani et al., 2000).

CLINICAL FEATURES

In 5 male patients with gout, Kelley et al. (1967) found a partial
deficiency of hypoxanthine-guanine phosphoribosyltransferase. Two
brothers in 1 family were 24 and 11 years old; three brothers in another
family were 42, 49, and 55 years old. In the first family,
nephrolithiasis began at age 6 or 7, followed in one by gouty arthritis
at age 13. In the 3 brothers, acute gouty arthritis began between ages
20 and 31 and 2 had had recurrent nephrolithiasis. The 2 brothers of the
first family had spinocerebellar derangement distinct from the
neurologic disorder of the Lesch-Nyhan syndrome. The characteristics of
the enzyme were the same in each family but different between families.
The differences concerned relative activities for guanine and
hypoxanthine and heat stability.

McDonald and Kelley (1971) presented evidence of genetic heterogeneity
in the Lesch-Nyhan syndrome. In the patient they reported, HPRT showed
altered kinetics. Among 425 cases of hyperuricemia with gout or uric
acid stone or both, Yu et al. (1972) found 7 with partial HPRT
deficiency and 5 of these were members of one family.

Andres et al. (1987) reported the case of a 12-year-old boy who
presented with acute renal failure accompanied by a disproportionate
increase of serum uric acid level and massive uric acid crystalluria.
After alkalinization and allopurinol therapy, serum uric acid and renal
function returned to normal. HPRT deficiency was found as the basis of
the abnormality.

Zoref-Shani et al. (2000) reported a 4.5-year-old boy who was admitted
to the hospital at the age of 3.5 years with acute renal failure due to
uric acid nephropathy. A streptococcal throat infection and fever were
present at the same time and may have been precipitating or contributing
factors. The precise nature of the DNA change was not described. The
authors stated that the underlying HPRT mutation was unique in that the
specific activity in HPRT and erythrocyte and fibroblast lysates was
normal, but the rate of uptake of hypoxanthine into nucleotides of
intact cultured fibroblasts was markedly reduced (23% of normal). Other
metabolic features of the mutation were described as well. With
allopurinol treatment, the patient had had no further problems and was
developing normally at 5 years of age.

Srivastava et al. (2002) reported the case of a 12-year-old boy who
presented with recurrent acute renal failure from hyperuricemia and had
no phenotypic features of Lesch-Nyhan syndrome. Acute infectious
mononucleosis may have triggered the acute renal failure, and treatment
with allopurinol prevented further episodes. Unlike the cells from
patients with Lesch-Nyhan syndrome, the in vitro cultures of this
patient's T lymphocytes did not proliferate in the presence of purine
analog 6-thioguanine.

MOELCULAR GENETICS In a patient with recurrent acute renal failure

from hyperuricemia, Srivastava et al. (2002) identified a novel HPRT
missense mutation (308000.0059).

*FIELD* RF
1. Andres, A.; Praga, M.; Ruilope, L. M.; Martinez, J. M.; Millet,
V. G.; Bello, I.; Rodicio, J. L.: Partial deficit of hypoxanthine
guanine phosphoribosyl transferase presenting as acute renal failure. Nephron 46:
179-181, 1987.

2. Kelley, W. N.; Rosenbloom, F. M.; Henderson, J. F.; Seegmiller,
J. E.: A specific enzyme defect in gout associated with overproduction
of uric acid. Proc. Nat. Acad. Sci. 57: 1735-1739, 1967.

3. McDonald, J. A.; Kelley, W. N.: Lesch-Nyhan syndrome: altered
kinetic properties of mutant enzyme. Science 171: 689-691, 1971.

4. Srivastava, T.; O'Neill, J. P.; Dasouki, M.; Simckes, A. M.: Childhood
hyperuricemia and acute renal failure resulting from a missense mutation
in the HPRT gene. Am. J. Med. Genet. 108: 219-222, 2002.

5. Yu, T.-F.; Balis, M. E.; Krenitsky, T. A.; Dancis, J.; Silvers,
D. N.; Elion, G. B.; Gutman, A. B.: Rarity of X-linked partial hypoxanthine-guanine
phosphoribosyltransferase deficiency in a large gouty population. Ann.
Intern. Med. 76: 255-264, 1972.

6. Zoref-Shani, E.; Feinstein, S.; Frishberg, Y.; Bromberg, Y.; Sperling,
O.: Kelley-Seegmiller syndrome due to a unique variant of hypoxanthine-guanine
phosphoribosyltransferase: reduced affinity for 5-phosphoribosyl-1-pyrophosphate
manifested only at low, physiological substrate concentrations. Biochim.
Biophys. Acta 1500: 197-203, 2000.

*FIELD* CS
INHERITANCE:
X-linked recessive

GENITOURINARY:
[Kidneys];
Nephrolithiasis;
Renal failure

SKELETAL:
[Feet];
Gout

LABORATORY ABNORMALITIES:
Hyperuricemia;
Hyperuricosuria

MISCELLANEOUS:
Partial deficiency of hypoxanthine phosphoribosyltransferase (HPRT,
78% activity)

MOLECULAR BASIS:
Caused by mutation in the hypoxanthine phosphoribosyltransferase gene
(HPRT1, 308000.0001)

*FIELD* CD
Ada Hamosh: 4/5/2001

*FIELD* ED
joanna: 05/19/2008
joanna: 4/5/2001

*FIELD* CN
Deborah L. Stone - updated: 4/11/2002

*FIELD* CD
Ada Hamosh: 4/4/2001

*FIELD* ED
carol: 03/28/2012
carol: 4/11/2002
carol: 4/11/2001
carol: 4/10/2001
mcapotos: 4/6/2001
carol: 4/4/2001

MIM 308000
*RECORD*
*FIELD* NO
308000
*FIELD* TI
*308000 HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1; HPRT1
HPRT;;
HGPRT
*FIELD* TX
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DESCRIPTION

HPRT1 has a central role in the generation of purine nucleotides through
the purine salvage pathway. HPRT1 encodes hypoxanthine
phosphoribosyltransferase (EC 2.4.2.8), which catalyzes conversion of
hypoxanthine to inosine monophosphate and guanine to guanosine
monophosphate via transfer of the 5-phosphoribosyl group from
5-phosphoribosyl 1-pyrophosphate (Keebaugh et al., 2007).

CLONING

Jolly et al. (1982) isolated a genomic clone partially encoding human
HPRT. Jolly et al. (1983) cloned a full-length 1.6 kb cDNA of a human
mRNA coding for HPRT into an SV40-based expression vector and determined
its full nucleotide sequence.

GENE STRUCTURE

Patel et al. (1986) reported that the HPRT gene is about 44 kb long and
contains 9 exons; see also Kim et al. (1986) and Melton et al. (1984).

MAPPING

X-linkage was first suggested by Hoefnagel et al. (1965) and was
supported by a rapidly accumulated series of families with deficiency of
HPRT. Rosenbloom et al. (1967) and Migeon et al. (1968) demonstrated 2
populations of fibroblasts, as regards the relevant enzyme activity, in
heterozygous females, thus providing support both for X-linkage and for
the Lyon hypothesis. Studies using human-mouse somatic cell hybrids
indicated, by reasoning similar to that used for locating the thymidine
kinase locus to chromosome 17 (188300), that the HPRT locus is on the X
chromosome (Nabholz et al., 1969). Silvers et al. (1972) demonstrated
mosaicism by study of hair roots in women heterozygous for the
Lesch-Nyhan syndrome (LNS; 300322), which is due to complete deficiency
of HPRT. Francke et al. (1976) studied the frequency of new mutations
among affected males. The Lesch-Nyhan syndrome is particularly favorable
for this purpose because no affected males reproduce, the diagnosis is
unequivocal and cases come readily to attention, and particularly
because heterozygosity can be demonstrated in females by the existence
of 2 populations of cultured fibroblasts. There were few new mutations,
contrary to the expected one-third. On the other hand, about one-half of
heterozygous females were new mutations, as is predicted by theory. The
finding may indicate a higher frequency of mutation in males than in
females. Another possibility is the role of somatic and half-chromatid
mutations (Gartler and Francke, 1975). New mutation cases of
heterozygous females had elevated parental age. Vogel (1977) reviewed
the evidence concerning hemophilia and the Lesch-Nyhan syndrome leading
to the conclusion that the mutation rate is higher in males than in
females. Evidence that the mutation rate for the Lesch-Nyhan disease may
be higher in males than in females was reviewed by Francke et al. (1976)
and criticized by Morton and Lalouel (1977). Francke et al. (1977)
answered the criticism. Strauss et al. (1980) showed that females
heterozygous for the Lesch-Nyhan mutation have 2 populations of
peripheral blood lymphocytes with regard to sensitivity to 6-thioguanine
inhibition of tritiated thymidine incorporation following
phytohemagglutinin stimulation. Henderson et al. (1969) concluded that
the locus for HPRT is closely linked to the Xg (314700) locus; Greene et
al. (1970) concluded, however, that the HPRT and Xg loci 'are sufficient
distance from each other on the human X chromosome that linkage cannot
be detected.' Nyhan et al. (1970) observed a sibship in which both HPRT
deficiency and G6PD deficiency (300908) were segregating and found 2
recombinants out of 4. Nyhan et al. (1970) also found that heterozygotes
had normal levels of HPRT in red cells. They interpreted this as
indicating a selective advantage of G6PD-normal over G6PD-deficient
cells. (In adrenoleukodystrophy (300100), it is the mutant cell that
enjoys the selective advantage.)

In mouse-man hybrid cells, when the mouse parent cell is of the type
called RAG which is resistant to 8-azaguanine because of a deficiency of
HPRT, the human form of HPRT is required in order for the hybrid cells
to survive in HAT selective medium. In over 100 clones of human-RAG
hybrid cells maintained in HAT, Ruddle (1971) saw without exception
persistence of human G6PD activity. This strongly indicated either close
linkage of the HPRT and G6PD loci or a very low incidence of
X-chromosome breakage and rearrangement. Emmerson et al. (1974) excluded
close linkage of the HPRT and the deutan colorblindness (303800) loci.
That the HPRT locus is X-linked in the mouse also was indicated by
Epstein (1972) finding that the activity of the enzyme at the 2-cell
stage in the XO product is half that in the XX. No difference is
observed in late morula and blastocyst stage. G6PD and HPRT are linked
in the Chinese hamster (Rosenstraus and Chasin, 1975) and presumably are
on the X chromosome as in man. By study of cell hybrids, Shows et al.
(1976) found that HPRT and G6PD are closely linked in the muntjac deer.
From study of radiation-induced segregants (irradiated human cells
'rescued' by fusion with hamster cells), Goss and Harris (1977) showed
that the order of the 4 loci is PGK: alpha-GAL: HPRT: G6PD and that the
3 intervals between these 4 loci are, in relative terms, 0.33, 0.30, and
0.23. Alpha-GAL, HPRT, PGK (172270), and G6PD were found to be X-linked
in rabbit hybrid cell studies (Cianfriglia et al., 1979; Echard and
Gillois, 1979). By comparable methods, Hors-Cayla et al. (1979) found
them to be X-linked also in cattle. According to cell hybridization
studies, HPRT, G6PD and PGK, are also X-linked in the pig (Gellin et
al., 1979) and in sheep (Saidi et al., 1979). Francke and Taggart (1979)
assigned HPRT and alpha-GAL to the X chromosome in the Chinese hamster
by study of mouse-Chinese hamster hybrid cells. It is remarkable that
although the HPRT and G6PD loci appear from physical mapping to be
closely situated, family studies indicate considerable recombination
(Francke et al., 1974). Studying X-autosome translocations in somatic
cell hybrids, Pai et al. (1980) showed that a breakpoint at the junction
of Xq27-q28 separates HPRT from G6PD. G6PD is distally situated at Xq28.
They localized HPRT to the segment between Xq26 and Xq27. Since the G6PD
locus is assigned to the terminal band of the long arm of the X (Xq28)
and HPRT to Xq27 and since the fragile site is located at the interface
between these 2 bands, may there be a 'hotspot' for crossing-over in the
segment of the X chromosome between the HPRT and G6PD loci? Fenwick
(1980) assigned the HPRT, G6PD, and PGK loci to the short arm of the
Chinese hamster X chromosome. Three pseudogenes, located on chromosomes
3, 5 and 11, have been identified (Stout and Caskey, 1984). Dobrovic et
al. (1987) identified a RFLP for the HPRT pseudogene on chromosome 3
(HPRTP1).

MOLECULAR GENETICS

Gibbs and Caskey (1987) used the ribonuclease A cleavage procedure, with
a polyuridylic acid-paper affinity chromatography step, to identify the
mutation lesions in the HPRT mRNA of patients with Lesch-Nyhan syndrome.
Of 14 patients chosen because no HPRT Southern or Northern blotting
pattern changes had been found, 5 were shown to have a distinctive
ribonuclease A cleavage pattern in messenger RNA. This method makes it
possible to assay for point mutation. The method had been used to
characterize beta-globin mutations in genomic DNA (Myers et al., 1985)
and KRAS variants in RNA from tumor cell lines. The ribonuclease A
cleavage assays are based on the fact that some single-base mismatch
sites in RNA hybrids with RNA or DNA will be cleaved by RNase A.
Cleavage occurs because of the single-stranded status of a region within
the hybrid. Since Southern and Northern blots show rearrangements in
about 15% of cases, combination of these methods with the ribonuclease A
cleavage method permits identification of abnormality in about 50% of
cases. Simpson et al. (1988) described a method of PCR (polymerase chain
reaction) for cloning and sequencing specific human HPRT cDNAs for
mutation analysis. Yang et al. (1984) found that the mutations in 7
Lesch-Nyhan patients were different. They demonstrated how it is
possible to trace the origin of new mutations by molecular genetic
methods. Gibbs et al. (1989) used automated direct DNA sequence analysis
of amplified HPRT cDNA to detect and characterize nucleotide alterations
in 15 independent mutations causing HPRT deficiency. Davidson et al.
(1989) used the PCR method to identify the mutations in HPRT mRNA from
B-lymphoblasts derived from 10 deficient individuals. Six contained
single point mutations, 3 contained deletions, and 1 contained a single
nucleotide insertion. Several of these mutations mapped near previously
identified HPRT variants and are located in evolutionarily conserved
regions of the molecule. Edwards et al. (1990) reported the complete
sequence of 57 kb of DNA at the HPRT locus. Ogasawara et al. (1989)
studied a 9-year-old girl with typical biochemical and behavioral
characteristics of the Lesch-Nyhan syndrome. Cytogenetic and carrier
studies showed structurally normal chromosomes in the patient and her
parents and demonstrated that the mutation arose through a de novo
gametic event. DNA studies showed a microdeletion that occurred in a
maternal gamete and involved the entire HPRT gene. However, in addition
to this, by study of somatic cell hybrids generated to separate maternal
and paternal X chromosomes, Ogasawara et al. (1989) showed that there
was a nonrandom inactivation of the cytogenetically normal paternal X
chromosome. Specifically, 2 other X-linked enzymes, phosphoglycerate
kinase and G6PD, were expressed only in somatic cell hybrid cells that
contained the maternal X chromosome. Furthermore, comparison of
methylation patterns within a region of the HPRT gene known to be
important in gene regulation showed differences between the DNA of the
father and that of the patient, in keeping with an active HPRT locus in
the father and an inactive HPRT locus in the patient.

In Southern blot patterns, Sinnett et al. (1988) found no evidence of
major structural alterations in the HPRT gene in 3 French Canadian
families with LNS. Northern analysis using HPRT cDNA as a probe showed
no hybridizing RNA in an affected member of 1 family, whereas
normal-sized mRNA was expressed at a very low level in the second family
and at a level comparable to the normal in the third. These data and
other information presented here indicate the heterogeneity of LNS
resulting from point mutations or small DNA deletions or rearrangements,
which may affect transcription, stability, or integrity of the HPRT
message. Seegmiller (1989) gave a useful overview of the substantial
contributions of the Lesch-Nyhan syndrome to the understanding of purine
metabolism, thus illustrating the garrodian principle of the usefulness
of rare genetic diseases to the understanding of biology and medicine.

In reporting lesions in the HPRT gene, the initiation methionine codon
has been counted as position 1 in some reports (e.g., Wilson et al.,
1983; Fujimori et al., 1988), whereas the codon for the first amino acid
of the mature protein has been used in others (e.g., Gibbs et al.,
1989). In the listing that follows, the initiation methionine codon is
counted as number 1 throughout.

See Rossiter et al. (1991) for a tabulation of HPRT mutations causing
Lesch-Nyhan syndrome. A notable feature of the list is the great variety
of mutations that can cause the Lesch-Nyhan syndrome and the rarity of
'repeat' mutations: HPRT London (308000.0010), a cause of precocious
gout, occurred in 2 unrelated persons; only the his203-to-asp mutation
(308000.0019) had been found in 2 unrelated LNS patients.

Sculley et al. (1992) reviewed the mutations involving the coding region
of HPRT. These included 32 that predictably cause changes in the size of
the translated protein and 38 that represent mutations causing a single
amino acid substitution. They commented that in the absence of precise
information on the 3-dimensional structure of the HPRT protein, it
remains difficult to determine any consistent correlation between
structure and function of the enzyme. Boyd et al. (1993) used
heteroduplex detection by hydrolink gel electrophoresis in screening for
mutations in families with Lesch-Nyhan syndrome.

In their Figure 3, Renwick et al. (1995) provided a summary map of the
HPRT mutations identified as causing disease in humans. Insertions and
deletions, as well as point mutations, were indicated. They stated that
17 microdeletions, most of them less than 20 bp, had been identified.
Gross alterations involving the HPRT gene found by Southern analysis
using cDNA probes included 3 total gene deletions, 3 partial gene
deletions involving the 3-prime portion, 2 duplications, and a possible
insertion. These gross DNA alterations accounted for only 12% of
reported Lesch-Nyhan cases. They reported another case, that of a 5-kb
deletion that had its end points in the first and third introns and was
responsible for Lesch-Nyhan syndrome.

Colgin et al. (2002) studied the HPRT gene to investigate the spectrum
and frequency of somatic mutations in kidney tubular epithelial cells.
Studies were done in primary tubular epithelial cell clones grown
directly from human kidney tissue. The authors found that mutant tubular
epithelial cells, recovered by growth in the purine analog 6-thioguanine
(TG), were surprisingly frequent. Mutant frequency increased
approximately 1% per year of donor age and was 10-fold or more higher in
kidney than in peripheral blood T lymphocytes of normal, age-matched
donors. Most TG-resistant kidney tubular epithelial cells from single
donors contained different HPRT mutations. A high proportion of the
mutations represented unreported HPRT base substitutions, 1-bp
deletions, and multiple mutations. This spectrum of somatic mutations
differed from HPRT mutations found in human peripheral blood T
lymphocytes and from germline HPRT mutations identified in Lesch-Nyhan
syndrome or hyperuricemia patients. The results indicated that DNA
damage and mutagenesis may have unusual features in kidney tubular
epithelium and that somatic mutation may play a more important role in
human kidney disease than previously appreciated.

PATHOGENESIS

Ceballos-Picot et al. (2009) demonstrated that HPRT deficiency
influences early developmental processes controlling the dopaminergic
phenotype. Microarray methods and quantitative PCR were applied to 10
different HPRT-deficient sublines derived from the hybrid MN9D cell
line, derived from somatic fusion of embryonic mouse primary midbrain
dopaminergic neurons and a mouse neuroblastoma cell line. There were
consistent increases in mRNAs for engrailed-1 (EN1; 131290) and -2 (EN2;
131310), transcription factors known to play a role in the specification
and survival of dopamine neurons. The increases in mRNAs were
accompanied by increases in engrailed proteins, and restoration of HPRT
reverted engrailed expression towards normal levels. The functional
relevance of the abnormal developmental molecular signature of the
HPRT-deficient MN9D cells was evident in impoverished neurite outgrowth
when the cells were forced to differentiate chemically. These
abnormalities were also seen in HPRT-deficient sublines from the
SK-N-BE(2)-M17 human neuroblastoma line, and overexpression of engrailed
was documented in primary fibroblasts from patients with Lesch-Nyhan
disease. Ceballos-Picot et al. (2009) concluded that HPRT deficiency may
affect dopaminergic neurons by influencing early developmental
mechanisms.

EVOLUTION

Using comparative mapping and sequencing, in conjunction with database
analysis, Keebaugh et al. (2007) showed that the HPRT gene family
expanded as a result of ancient vertebrate-specific duplications and is
composed of 3 groups: HPRT1, PRTFDC1 (610751) and Hprt1l, which is found
only in fish. These 3 gene groups have distinct rates of evolution and
potentially divergent function. Keebaugh et al. (2007) noted that HPRT1
is an X-linked gene in placental mammals and marsupials, whereas in
other vertebrates it is located on an autosome.

ANIMAL MODEL

Hooper et al. (1987) and Kuehn et al. (1987) independently reported
success in generating HPRT-deficient male mice by injecting into normal
embryos pluripotential stem cells which had first been selected as
HPRT-negative in tissue culture. They found that the germline was
colonized by these cultured cells with resulting germline chimerism and
production of female offspring heterozygous for HPRT deficiency. In this
way it was possible to derive strains of mutant mice having the same
biochemical defect as Lesch-Nyhan patients. The availability of such
mice should permit study of the molecular basis of the phenotype in this
disorder. HPRT is an ideal gene for these studies because it is
expressed by all cells and only 1 copy needs to be eliminated in XY cell
lines to produce enzyme deficiency; because the gene presents a
reasonable target size (34 kb) and cloned probes enable the sites of
mutation to be mapped; and particularly because a powerful technique is
available for selecting HPRT-negative cells. Since these cells, unlike
HPRT-positive cells, are unable to salvage free purine bases, they are
not killed when toxic purine analogs such as 6-thioguanine and
8-azoguanine are added to the culture medium. The method used by these
workers depended on embryonic stem (ES) cells that can still enter the
germline after genetic manipulation in culture. Doetschman et al. (1987)
used homologous recombination between the HPRT gene and exogenous DNA
for targeted correction of the HPRT locus in the ES cell line that had
previously been isolated and used to produce an HPRT-deficient mouse.
Koller et al. (1989) injected the 'corrected' embryonic stem cells into
blastocysts which were introduced into pseudopregnant female mice to
complete their development. Nine chimeric pups (6 males, 3 females) were
obtained. Two of the males transmitted the embryonic stem cell genome
containing the alteration in the HPRT gene to their offspring at high
frequencies. Using a mouse model of HPRT deficiency, Monk et al. (1987,
1990) showed that sexing and diagnosis of the deficiency could be
performed in preimplantation embryos by biochemical microassay. The
diagnoses were sufficiently rapid that freezing of the embryos before
transfer was not necessary. Sexing was possible because both X
chromosomes are active in female morulae and the blastomeres sampled
from female preimplantation embryos have twice as much X-encoded HPRT
activity as do blastomeres from male embryos. Wu and Melton (1993)
examined the question of why HPRT-deficient mice generated using the
embryonic stem cell system show no spontaneous behavioral abnormalities
characteristic of Lesch-Nyhan syndrome. They suspected that mice are
more tolerant of HPRT deficiency because they are more reliant on
adenine phosphoribosyltransferase (APRT; 102600) than HPRT for their
purine salvage. Pursuing this idea, they administered an APRT inhibitor
to HPRT-deficient mice and induced persistent self-injurious behavior.

Engle et al. (1996) bred HPRT/APRT doubly deficient mice in an attempt
to induce behavioral manifestations characteristic of Lesch-Nyhan
syndrome in humans. They noted that HPRT-deficient mice showed no
behavioral abnormalities. The APRT/HPRT-deficient mice who were void of
any purine salvage pathways showed no novel behavioral phenotype.

*FIELD* AV
.0001
GOUT, HPRT-RELATED
HPRT ANN ARBOR
HPRT, ILE132MET

Fujimori et al. (1988) showed that the change in HPRT(Ann Arbor) is a
single nucleotide change (T-to-G) at nucleotide position 396. This
transversion predicts an amino acid substitution from isoleucine (ATT)
to methionine (ATG) in codon 132, which is located within the putative
PRPP-binding site of HPRT. HPRT(Ann Arbor) was identified in 2 brothers
with hyperuricemia and nephrolithiasis (300323).

.0002
GOUT, HPRT-RELATED
HPRT ARLINGTON
HPRT, ASP80VAL

In a male with gout and partial HPRT deficiency (300323), Davidson et
al. (1989) found an A-to-T change at nucleotide 239, changing aspartic
acid-80 to valine.

.0003
GOUT, HPRT-RELATED
HPRT ASHVILLE
HPRT, ASP201GLY

Davidson et al. (1989) identified an A-to-G transition at nucleotide
602, leading to a substitution of glycine for aspartic acid as amino
acid 201 in a variant referred to as HPRT(Ashville). The man with this
mutant had severe precocious gout and uric acid nephrolithiasis, due to
overproduction of uric acid, and partial HPRT deficiency (300323).

.0004
LESCH-NYHAN SYNDROME
HPRT CHICAGO
HPRT, 1-BP INS, 56T

In a patient with LNS (300322), Davidson et al. (1989) demonstrated
insertion of 1 nucleotide, a T, as either no. 56, 57, or 58. This led to
a change of CCTTGA to CCTTTGA and termination of translation at asp20.

.0005
LESCH-NYHAN SYNDROME
HPRT CONNERSVILLE
HPRT, EX8DEL

In a patient with LNS (300322), Davidson et al. (1989) found deletion of
nucleotides 532-609 (all of exon 8) causing loss of phe178 to asn203. A
change in reading frames results in a stop codon 15 nucleotides
downstream from the junction between exons 7 and 9.

.0006
LESCH-NYHAN SYNDROME
HPRT DETROIT
HPRT, LEU41PRO

In a patient with LNS (300322), Davidson et al. (1989) found that a
change of nucleotide 122 from T to C caused substitution of proline for
leu41.

.0007
LESCH-NYHAN SYNDROME
HPRT EVANSVILLE
HPRT, 24AA+

In a patient with LNS (300322), Davidson et al. (1989) found an HPRT
protein abnormally long by 24 amino acids, resulting from change in
nucleotides 643 to 663 which code for the last 4 amino acids and the
stop codon. This mutation was also reported by Gibbs et al. (1990) in
cell line RJK894. (RJK = Robert J. Kleberg, a major benefactor of the
Institute of Medical Genetics at Baylor College of Medicine.)

.0008
LESCH-NYHAN SYNDROME
HPRT FLINT
HPRT, PHE74LEU

In a patient with LNS (300322), Davidson et al. (1988) found a C-to-A
change that converted phenylalanine-74 to leucine. (The cell line is
also known as RJK896 (Gibbs et al., 1990).) This mutation is the same as
that in HPRT Perth, which was identified as an independent mutation by
Sculley et al. (1991) in a patient with Lesch-Nyhan syndrome in
Australia.

.0009
LESCH-NYHAN SYNDROME
HPRT KINSTON
HPRT, ASP194ASN AND ASP193ASN

HPRT(Kinston) has a G-to-A change resulting in substitution of
asparagine for aspartic acid as amino acid 194 (Wilson and Kelley,
1983). Gibbs et al. (1990) described an asp193-to-asn substitution in
cell line RJK2188 from a patient with LNS (300322). This is the same as
HPRT Kinston; Gibbs et al. (1990) used the numbering system not counting
the initial methionine, whereas Wilson and Kelley (1983) did use it.

.0010
GOUT, HPRT-RELATED
HPRT LONDON
HPRT, SER110LEU

Wilson et al. (1983) found substitution of leucine for serine at amino
acid 109 in HPRT(London). Davidson et al. (1988) showed that
HPRT(London), observed in 2 apparently unrelated individuals and
resulting in partial HPRT deficiency and gout (300323), is the result of
a mutation that causes substitution of leucine for serine at amino acid
110. The DNA change is a C-to-T transition at bp 329. This transition
creates an HpaI site in exon 4 of the HPRT gene. This is explicable by
change from UCA to UUA in codon 109.

.0011
LESCH-NYHAN SYNDROME
HPRT MICHIGAN
HPRT, 3-BP DEL, VAL179DEL

In a case of LNS (300322), Davidson et al. (1989) showed that the
mutation is a deletion of nucleotides 535-537 resulting in loss of
valine 179.

.0012
LESCH-NYHAN SYNDROME
HPRT MIDLAND
HPRT, VAL130ASP

In a patient with Lesch-Nyhan syndrome (300322), Davidson et al. (1988)
and Gibbs et al. (1989) found a T-to-A change resulting in substitution
of aspartic acid for valine-130.

.0013
GOUT, HPRT-RELATED
HPRT MILWAUKEE
HPRT, ALA161SER

In a patient with partial HPRT deficiency and gout (300323), Davidson et
al. (1989) found a change of nucleotide 481 from G to T resulting in
substitution of alanine-161 by serine. (The cell line is RJK949 of Gibbs
et al. (1989).)

.0014
GOUT, HPRT-RELATED
HPRT MUNICH
HPRT, SER104ARG

By a combination of denaturing gradient gel electrophoresis and in vitro
DNA amplification, Cariello et al. (1988) localized a DNA mutation to a
given 100-bp region of the human genome and rapidly sequenced the DNA
without cloning. The mutation studied by Cariello et al. (1988),
HPRT(Munich), came from a patient with gout (300323); it was found to
represent a single basepair substitution, a C-to-A transversion at
basepair 312. (This was reported as 397 by Cariello et al. (1988)
because of a different system of numbering nucleotides.) Wilson and
Kelley (1984) defined it as a ser104-to-arg bp substitution by studies
of protein sequence, and Palella (1990) later determined the nucleotide
change as C-to-T.

.0015
LESCH-NYHAN SYNDROME
HPRT NEW BRITON
HPRT, PHE199VAL

In a case of LNS (300322), Davidson et al. (1989) showed that a T-to-G
change in nucleotide 595 produced a substitution of phe199 by valine.
(This is the same as cell line RJK950, studied by Gibbs et al. (1989).)

.0016
LESCH-NYHAN SYNDROME
HPRT NEW HAVEN
HPRT, GLY70GLU

In a case of LNS (300322), Davidson et al. (1989) showed that a G-to-A
change in nucleotide 209 resulted in substitution of gly70 by glutamic
acid.

.0017
LESCH-NYHAN SYNDROME
HPRT YALE
HPRT, GLY71ARG

In the mutant HPRT(Yale), discovered in a subject with LNS (300322),
Wilson et al. (1986) found normal mRNA in protein concentrations, no
residual catalytic activity, and cathodal migration upon PAGE. By
cloning and sequencing HPRT(Yale) cDNA, Fujimori et al. (1989) found a
single nucleotide substitution: G-to-C at nucleotide position 211. This
transversion predicted substitution of arginine for glycine at amino
acid position 71, explaining the cathodal migration of HPRT(Yale).
Inclusion of the bulky arginine side chain in place of glycine probably
disrupts protein folding.

.0018
LESCH-NYHAN SYNDROME
HPRT, GLN108TER

Gibbs et al. (1990) described this mutation in cell line RJK1930 from a
patient with LNS (300322).

.0019
LESCH-NYHAN SYNDROME
HPRT, HIS203ASP

Gibbs et al. (1989) described this mutation in cell line RJK1874 from a
patient with LNS (300322). Gibbs et al. (1990) found the same mutation
in an unrelated patient with LNS (RJK2019).

.0020
LESCH-NYHAN SYNDROME
HPRT, ARG44LYS

Gibbs et al. (1990) described this mutation in cell line RJK2163 from a
patient with LNS (300322).

.0021
LESCH-NYHAN SYNDROME
HPRT, ASP176TYR

Gibbs et al. (1990) described this mutation in cell line RJK2185 from a
patient with LNS (300322).

.0024
LESCH-NYHAN SYNDROME
HPRT, 2-BP DEL, GT

In cell line RJK1747 from a patient with LNS (300322), Gibbs et al.
(1990) found deletion of 2 nucleotides (GT) causing a frameshift.

.0026
LESCH-NYHAN SYNDROME
HPRT, 1-BP DEL, TTA-TA

In cell line RJK1939 from a patient with LNS (300322), Gibbs et al.
(1990) found deletion of 1 nucleotide (TTA-to-TA) resulting in a
frameshift.

.0027
LESCH-NYHAN SYNDROME
HPRT, 1-BP DEL, TTG-TG

In cell line RJK2019 from a patient with LNS (300322), Gibbs et al.
(1990) found deletion of 1 nucleotide (TTG-to-TG) resulting in a
frameshift.

.0028
LESCH-NYHAN SYNDROME
HPRT, 40-BP DEL

In cell line RJK2108 from a patient with LNS (300322), Gibbs et al.
(1990) found deletion of 40 nucleotides resulting in a frameshift.

.0029
LESCH-NYHAN SYNDROME
HPRT, IVS8DS, G-A, +5

In cell line RJK888 from a patient with LNS (300322), Gibbs et al.
(1990) found a G-to-A change of the fifth nucleotide in intron 8 causing
a defect in splicing because of the change in the donor site.

.0030
LESCH-NYHAN SYNDROME
HPRT, IVS8AS, ATAG-TTTG

In cell line RJK906 from a patient with LNS (300322), Gibbs et al.
(1990) found an ATAG-to-TTTG change in the last 4 nucleotides of intron
8. Interference with processing resulted from mutation in the acceptor
splice site.

.0031
LESCH-NYHAN SYNDROME
HPRT, IVS7DS, G-A, +5

In cell line RJK1934 from a patient with LNS (300322), Gibbs et al.
(1990) found a GTAAGT-to-GTAAAT change at the beginning of intron 7.
Interference with processing resulted from mutation in the donor splice
site. See 308000.0029 for the corresponding mutation in intron 8.

.0032
LESCH-NYHAN SYNDROME
HPRT, IVS1AS, A-T, -2

In cell line RJK1760 from a patient with LNS (300322), Gibbs et al.
(1990) found an AG-to-TG change in the last 2 nucleotides of intron 1.
Interference with processing resulted from mutation in the acceptor
splice site.

.0033
LESCH-NYHAN SYNDROME
HPRT, PRO176LEU

Davidson et al. (1989) referred to their observations concerning this
mutation. The substitution predicts loss in beta-turn structure and
change in hydrophilicity which may be essential to normal enzymatic
function since this and the Evansville and Milwaukee mutations have
greatly diminished or undetectable enzyme activity. (Davidson (1990)
identified the mutation as pro176leu rather than pro174leu as
published.)

.0034
GOUT, HPRT-RELATED
HPRT TORONTO
HPRT, ARG51GLY

In a patient with gout (300323), Wilson et al. (1983) found substitution
of glycine (GGA) for arginine-51 (CGA).

.0035
LESCH-NYHAN SYNDROME
HPRT FUJIMI
HPRT, ARG51TER

In a Japanese patient with Lesch-Nyhan syndrome (300322), Fujimori et
al. (1990) identified a change of codon 51 from CGA(arg) to TGA(stop).
The same codon, although a different nucleotide, is involved in
HPRT(Toronto). HPRT(Toronto) is associated with incomplete deficiency
leading to gout and not the Lesch-Nyhan syndrome.

.0036
LESCH-NYHAN SYNDROME, NEUROLOGIC VARIANT
HPRT MONTREAL
HPRT, MET56THR

Skopek et al. (1990) used DNA from peripheral blood T-lymphocytes to
demonstrate a single base substitution (T-to-C transition) at position
170 (exon 3). The predicted amino acid change was a substitution of
threonine for methionine-56. The probands were 2 male children in a
French Canadian family. Both had developmental delay, mainly motor in
nature, and were confined to a wheelchair by age 5. Neither had
aggressive behavior or self-mutilation (see 300322). HPRT activities
were 18% and 10% of parental values for the older and younger boy,
respectively.

.0037
LESCH-NYHAN SYNDROME
HPRT, MET143LYS

In patient GB (RJK1210) with LNS (300322), Gibbs et al. (1989) found a
TGC-to-AGC change at nucleotide 428 in exon 6, causing a met143-to-lys
substitution.

.0038
LESCH-NYHAN SYNDROME
HPRT, ARG170TER

In patient JC (RJK 974) with LNS (300322), Gibbs et al. (1989) found a
CGA-to-TGA change in codon 170. In a family containing at least 3 males
with Lesch-Nyhan syndrome, Marcus et al. (1992) identified a nonsense
mutation at the CpG site in the codon for arginine-169, by genomic PCR
and DNA sequencing in cultured fibroblasts. The recurrence of mutation
at this site in several unrelated Lesch-Nyhan families suggested
deamination of 5-methylcytosine as a mechanism for mutagenesis. The
level of HPRT mRNA in the fibroblasts of the patients was similar to
that in healthy controls, whereas HPRT enzyme activity was not
detectable. A noncarrier phenotype was found in hair follicle analyses
and fibroblast selection studies in 8-azaguanine and 6-thioguanine
medium in 3 of the obligatory female heterozygotes, whereas
X-inactivation mosaicism was demonstrated in 1 heterozygote. Marcus et
al. (1992) raised the possibility that the HPRT mutation was associated
with an undefined X-linked lethal mutation leading to the nonrandom
X-inactivation. The observation is of practical relevance for carrier
detection in other Lesch-Nyhan families. The mutation called ARG169TER
by Marcus et al. (1992) is the same as that numbered arg170-to-ter by
Gibbs et al. (1989). Tarle et al. (1991) found the same mutation. Marcus
et al. (1992) quoted Gibbs as having found 3 additional unrelated
patients with the same mutation which may account for about 15% of the
base substitution mutations identified so far.

De Gregorio et al. (2000) reported an Argentinian family in which a
22-year-old male and his 8-year-old sister had clinically identical
classic features of LNS. The mother and an older daughter were carriers
and had normal phenotypes. The affected sister was karyotypically normal
and heterozygous for the R169X mutation. She inherited the HPRT mutation
from her mother, but she had nonrandom inactivation of the paternal X
chromosome carrying the normal HPRT gene.

.0039
GOUT, HPRT-RELATED
HPRT, 13-BP DEL, 5-PRIME UTR

In patient RT (RJK 951) with gout (300323), Gibbs et al. (1989) found
deletion of 13 nucleotides of which the first was 12 nucleotides 5-prime
to the initiation codon. With the loss of the first nucleotide of the
initiation codon, initiation in-frame may have occurred downstream.

.0040
LESCH-NYHAN SYNDROME
HPRT, EX2DEL

In patient MG (RJK1780) with LNS (300322), Gibbs et al. (1990) found
deletion of exon 2.

.0041
LESCH-NYHAN SYNDROME
HPRT, EX4-9DEL

In patient EB (RJK849) with LNS (300322), Yang et al. (1984) found
deletion of exons 4 to 9, inclusive. No mRNA was found.

.0042
LESCH-NYHAN SYNDROME
HPRT, EX6-9DEL

In patient EB (RJK984) with LNS (300322), Stout and Caskey (1985) and
Gibbs et al. (1990) demonstrated deletion of exons 6 to 9, inclusive. No
mRNA was demonstrable.

.0043
LESCH-NYHAN SYNDROME
HPRT, EX9DEL

In cell line GM3467 from a patient with LNS (300322), Yang et al. (1984)
and Gibbs et al. (1990) demonstrated deletion of exon 9. No mRNA was
demonstrable.

.0044
LESCH-NYHAN SYNDROME
HPRT, DEL

In patient BM (RJK853) with LNS (300322), Yang et al. (1984) and Gibbs
et al. (1990) found deletion of the entire HPRT gene. Deletion of the
entire gene was found also in a female patient with LNS (Ogasawara et
al., 1989). No mRNA was present in either case.

.0045
LESCH-NYHAN SYNDROME
HPRT,1-BP INS, 207G

In patient CW (RJK866) with LNS (300322), Gibbs et al. (1989) found
insertion of a single guanine nucleotide at about nucleotide 207 of the
cDNA. The resulting frameshift produced a protein with 84 amino acids.

.0046
LESCH-NYHAN SYNDROME
HPRT, INV/DEL, EX6-9

In GM2227 from a patient with LNS (300322), Edwards and Caskey (1990)
found a complex rearrangement involving inversion and deletion of exons
6 to 9. No mRNA was found.

.0047
LESCH-NYHAN SYNDROME
HPRT, EX2-3DUP, IVS1DEL

In GM1662 and GM6804 from patients with LNS (300322), Yang et al.(1984,
1988) found a complex rearrangement involving duplication of exons 2 and
3 and deletion of intron 1. Increased size of mRNA was observed. Monnat
et al. (1992) demonstrated that the duplication in GM6804 was generated
by the nonhomologous insertion of duplicated HPRT DNA into HPRT intron
1. They found that the duplication was genetically unstable and had a
reversion rate approximately 100-fold higher than the rate of
duplication formation. Exons 2 and 3, together with 13.7 kb of
surrounding HPRT sequence, were duplicated.

.0048
GOUT, HPRT-RELATED
HPRT BRISBANE
HPRT, THR168ILE

In a patient with urate overproduction and gout (300323), Gordon et al.
(1990) found a C-to-T transition which predicted an amino acid
substitution of isoleucine for threonine at amino acid 168 of the HPRT
protein. The nucleotide substitution created a BamHI site, confirming a
RFLP previously observed in this patient. In red cell lysates, the
patient had approximately 10% of normal HPRT activity and 26% of
immunoidentical HPRT protein.

.0049
HPRT DEFICIENCY, PARTIAL
HPRT URANGAN
HPRT, GLY16SER

In a patient with partial HPRT deficiency (enzyme activity less than
0.1%; 300323), Sculley et al. (1991) identified a G-to-A mutation at
nucleotide 145 resulting in a substitution of serine for glycine-16.

.0050
HPRT DEFICIENCY, PARTIAL
HPRT TOOWONG
HPRT, GLY58ARG

In a patient with partial HPRT deficiency (enzyme activity = 10%;
300323), Sculley et al. (1991) identified a G-to-A mutation at
nucleotide 271 resulting in a substitution of arginine for glycine-58.

.0051
HPRT DEFICIENCY, PARTIAL
HPRT SWAN
HPRT, LEU78VAL

In a patient with partial HPRT deficiency (enzyme activity = 10%;
300323), Sculley et al. (1991) found a C-to-G mutation at nucleotide 331
resulting in substitution of valine for leucine-78.

.0052
LESCH-NYHAN SYNDROME
HPRT CHERMSIDE
HPRT, EX6DEL

In a patient with Lesch-Nyhan syndrome (300322), Gordon et al. (1991)
demonstrated a G-to-A transition in the first nucleotide of intron 6
resulting in deletion of the 83 bp comprising exon 6.

.0053
LESCH-NYHAN SYNDROME
HPRT COORPAROO
HPRT, 1-BP INS, 14823T

In a patient with Lesch-Nyhan syndrome (300322), Gordon et al. (1991)
identified an insertion of a T nucleotide at either nucleotide 14823 or
14824. This placed a stop codon in frame, resulting in premature
termination of translation of the HPRT mRNA.

.0054
GOUT, HPRT-RELATED
HPRT EDINBURGH
HPRT, ASP52GLY

Snyder et al. (1989) described 3 brothers who developed acute gouty
arthritis (300323) between ages 16 and 26 years. One brother had an
episode of renal failure at the age of 5 and one suffered an attack of
renal colic at age 12. None had evidence of neurologic disturbance but
the youngest had epileptic episodes. Lymphoblasts established from these
patients had detectable, but less than 2%, HPRT activity. Lightfoot et
al. (1992) demonstrated an A-to-G transition at base 155 in exon 3
predicting a change in aspartic acid 52 to glycine.

.0055
LESCH-NYHAN SYNDROME
HPRT TOKYO
HPRT, GLY140ASP

In a Japanese patient with Lesch-Nyhan syndrome (300322), Fujimori et
al. (1991, 1992) found a G-to-A transition at nucleotide 419 which
predicted a single amino acid substitution of an aspartic acid for a
glycine at position 140. The amino acid substitution was located within
the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region.

.0056
GOUT, HPRT-RELATED
HPRT MOOSE JAW
HPRT, ASP194GLU

Snyder et al. (1984) described a family in which 4 males had gout with
partial HPRT deficiency (300323) and reduced affinity of the enzyme for
PPRP. The proband was a slow learner and stutterer, but none of the 4
had major neurologic abnormalities. One had died of renal failure,
presumably due to gouty kidney at age 32. Called HPRT-Moose Jaw, the
mutation in this Canadian family was due to a C-to-G transversion at
nucleotide 582 (relative to initiation of translation) resulting in
substitution of aspartate-194 by glutamate. Lightfoot et al. (1994)
demonstrated that the K(m) of the mutant protein for hypoxanthine was
increased 12-fold and the apparent K(m) for PPRP was increased 44-fold.
Although the turnover number or k(cat) of the mutant protein was
equivalent to that of the wildtype, the catalytic efficiency of the
purified mutant protein was only 6% and 3% of that of the wildtype with
hypoxanthine and PPRP, respectively.

.0057
LESCH-NYHAN SYNDROME
HPRT PARIS
HPRT, TYR153TER

Van Bogaert et al. (1992) described a typical case of Lesch-Nyhan
syndrome (300322) in a female patient. Aral et al. (1996) demonstrated
that the molecular basis of HPRT deficiency in this patient was a
previously undescribed nucleotide substitution in exon 6. The gene,
designated HPRT Paris, showed a single nucleotide substitution from T to
G at base position 558, changing tyrosine-153 (TAT) to a stop codon
(TAG). The mother showed a normal HPRT sequence, indicating that the
mutation arose through a de novo gametic event. Allele-specific
amplification of exon 6 confirmed the single-base substitution and
showed that the patient was heterozygous. Investigation of X-chromosomal
inactivation by comparison of the methylation patterns of the patient's
DNA indicated a nonrandom pattern of X-chromosomal inactivation with
preferential inactivation of the maternal allele. Thus, the authors
concluded that the lack of HPRT activity in this female patient was the
result of a de novo point mutation in the paternal gene combined with
selective inactivation of the maternal gene.

.0058
LESCH-NYHAN SYNDROME
HPRT, 2969-BP DEL, NT970

In 2 Japanese patients with Lesch-Nyhan syndrome (300322), Mizunuma et
al. (2001) detected the identical large genomic deletion, which spanned
from an Alu sequence in a promoter region to another Alu sequence in
intron 1, a length of 2,969 basepairs including exon 1. They concluded
that this identical deletion in the HPRT1 gene in 2 patients was derived
from recurrent events of genomic recombination, since mitochondrial DNA
showed differences in the 2 cases. Mitochondrial DNA was considered a
valid gauge, since HPRT1 mutations and mitochondrial DNA cotransmitted
from carrier mother to offspring. The same Alu-mediated deletion of
HPRT1 had not been reported among somatic mutations at this locus,
suggesting that the region of the HPRT1 gene flanked by Alu sequences is
a mutation hotspot in the germline but not in somatic cells.

.0059
HPRT DEFICIENCY, PARTIAL
HPRT, LEU65PHE

In a 12-year-old boy with partial HPRT deficiency (300323) who presented
with recurrent acute renal failure from hyperuricemia and had no
phenotypic features of Lesch-Nyhan syndrome, Srivastava et al. (2002)
identified a C-to-T transition at nucleotide 193 in exon 3 of the HPRT
gene, resulting in a leu65-to-phe substitution. Red blood cell lysates
had less than 10% of normal HPRT activity.

.0060
LESCH-NYHAN SYNDROME, NEUROLOGIC VARIANT
GOUT, HPRT-RELATED, INCLUDED
HPRT, ARG48HIS

In 9 patients from 7 unrelated families with the neurologic variant of
Lesch-Nyhan syndrome (see 300322), Sampat et al. (2011) identified a
143G-A transition in the HPRT gene, resulting in an arg48-to-his (R48H)
substitution in an alpha-2 helix at the interface between dimerization
of the protein. An additional patient with hyperuricemia and
impulsive/oppositional behavior, whom the authors classified as having
HPRT-related hyperuricemia (300323), also carried the mutation. The
mutation likely arose independently multiple times, because it occurred
at a CpG motif. There was almost no detectable HPRT enzyme activity in
patient erythrocytes, but there was some residual activity in patient
fibroblasts. Kinetic studies in E. coli showed that the mutant enzyme
had normal affinity for hypoxanthine and guanine, but V(max) was
decreased by 33% and 37% for those substrates, respectively, compared to
wildtype. However, additional studies showed that the mutant protein had
poor thermal stability, with only 16% residual activity at 37 degrees C
and undetectable activity at 55 degrees C, which may have explained the
variable phenotypic consequences in mutation carriers.

*FIELD* SA
Benke et al. (1973); Benke et al. (1973); Bland (1968); Brennand
et al. (1982); Caskey and Kruh (1979); Chinault and Caskey (1984);
Cox et al. (1970); Dancis et al. (1973); Davidson et al. (1988); Davidson
et al. (1989); Davidson et al. (1991); Demars et al. (1969); Dempsey
et al. (1983); Emmerson et al. (1972); Ernst et al. (1996); Fox et
al. (1975); Francke and Taggart (1979); Fujimori et al. (1992); Fujimori
et al. (1991); Gibbs et al. (1984); Graham et al. (1996); Greene
(1972); Gutensohn and Jahn (1979); Hashmi and Miller (1976); Holland
et al. (1983); Kelley et al. (1969); Kelley et al. (1967); Kogut et
al. (1970); Lesch and Nyhan (1964); Lloyd et al. (1981); Malleson
et al. (1996); McDonald and Kelley (1972); McDonald and Kelley (1971);
McKeran et al. (1975); Migeon (1970); Miller et al. (1983); Newcombe
et al. (1966); Nussbaum et al. (1983); Nyhan et al. (1965); Nyhan
et al. (1967); Nyhan and Wong (1996); Race and Sanger (1968); Rijksen
et al. (1981); Rosenbloom et al. (1967); Sass et al. (1965); Seegmiller
et al. (1967); Shapiro et al. (1966); Shows and Brown (1975); Sperling
et al. (1970); Strauss et al. (1981); Toyo-Oka et al. (1975); Willers
et al. (1977); Wilson et al. (1981); Wilson et al. (1982); Wilson
et al. (1983); Wilson et al. (1983); Wilson et al. (1983); Winter
(1980); Wong et al. (1996); Yang et al. (1988); Yu et al. (1972);
Zannis et al. (1980); Zoref and Sperling (1979); Zoref-Shani et al.
(2000)
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24. Dobrovic, A.; Gareau, P.; Seifert, A.-M.; Messing, K.; Bradley,
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25. Doetschman, T.; Gregg, R. G.; Maeda, N.; Hooper, M. L.; Melton,
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27. Edwards, A.; Caskey, C. T.: Personal Communication. Houston,
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36. Francke, U.; Bakay, B.; Connor, J. D.; Coldwell, J. G.; Nyhan,
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39. Francke, U.; Taggart, R. T.: Regional mapping of SOD-1 on mouse
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40. Francke, U.; Taggart, R. T.: Assignment of the gene for cytoplasmic
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*FIELD* CN
Cassandra L. Kniffin - updated: 4/26/2011
George E. Tiller - updated: 3/30/2010
Patricia A. Hartz - updated: 2/9/2007
Deborah L. Stone - updated: 4/11/2002
Victor A. McKusick - updated: 3/5/2002
Victor A. McKusick - updated: 11/29/2001
Victor A. McKusick - updated: 2/15/2001
Victor A. McKusick - updated: 2/13/2001
Victor A. McKusick - updated: 2/18/1999
Victor A. McKusick - updated: 8/13/1997
Victor A. McKusick - updated: 6/18/1997
Moyra Smith - updated: 1/7/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 10/24/2013
wwang: 5/12/2011
ckniffin: 4/26/2011
carol: 8/12/2010
carol: 5/18/2010
terry: 5/12/2010
wwang: 3/31/2010
terry: 3/30/2010
alopez: 3/19/2010
terry: 6/3/2009
terry: 3/31/2009
wwang: 11/13/2008
carol: 8/10/2007
mgross: 2/9/2007
carol: 5/27/2005
cwells: 11/5/2003
carol: 4/11/2002
mgross: 3/8/2002
terry: 3/5/2002
carol: 1/15/2002
mcapotos: 12/12/2001
terry: 11/29/2001
mcapotos: 4/6/2001
carol: 4/5/2001
carol: 4/4/2001
cwells: 2/21/2001
terry: 2/15/2001
cwells: 2/15/2001
cwells: 2/14/2001
terry: 2/13/2001
carol: 1/18/2000
carol: 9/10/1999
mgross: 2/26/1999
mgross: 2/24/1999
terry: 2/18/1999
dkim: 12/15/1998
dkim: 12/10/1998
terry: 6/18/1998
terry: 6/5/1998
terry: 6/4/1998
terry: 8/13/1997
alopez: 7/29/1997
alopez: 7/8/1997
carol: 6/23/1997
jenny: 6/23/1997
mark: 6/18/1997
mark: 1/11/1997
jamie: 1/7/1997
mark: 1/7/1997
jamie: 12/19/1996
terry: 12/13/1996
terry: 8/15/1996
terry: 7/29/1996
terry: 6/28/1996
mark: 6/24/1996
terry: 6/12/1996
terry: 3/26/1996
mark: 2/1/1996
mark: 1/31/1996
terry: 1/31/1996
terry: 1/25/1996
mark: 9/20/1995
carol: 10/18/1994
davew: 7/26/1994
pfoster: 5/12/1994
terry: 4/27/1994
warfield: 4/20/1994

RBCC Red Blood Cell Collection

Full text data of HPRT1