Full text data of QDPR
QDPR
(DHPR)
[Confidence: low (only semi-automatic identification from reviews)]
Dihydropteridine reductase; 1.5.1.34 (HDHPR; Quinoid dihydropteridine reductase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Dihydropteridine reductase; 1.5.1.34 (HDHPR; Quinoid dihydropteridine reductase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P09417
ID DHPR_HUMAN Reviewed; 244 AA.
AC P09417; A8K158; Q53F52; Q9H3M5;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 28-NOV-2006, sequence version 2.
DT 22-JAN-2014, entry version 160.
DE RecName: Full=Dihydropteridine reductase;
DE EC=1.5.1.34;
DE AltName: Full=HDHPR;
DE AltName: Full=Quinoid dihydropteridine reductase;
GN Name=QDPR; Synonyms=DHPR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-51.
RX PubMed=3031582; DOI=10.1093/nar/15.5.1921;
RA Dahl H.-H.M., Hutchison W., McAdam W., Wake S., Morgan F.J.,
RA Cotton R.G.H.;
RT "Human dihydropteridine reductase: characterisation of a cDNA clone
RT and its use in analysis of patients with dihydropteridine reductase
RT deficiency.";
RL Nucleic Acids Res. 15:1921-1932(1987).
RN [2]
RP SEQUENCE REVISION TO 51.
RA Dahl H.-H.M.;
RL Submitted (JUL-1987) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-51.
RX PubMed=3033643; DOI=10.1073/pnas.84.10.3329;
RA Lockyer J., Cook R.G., Milstien S., Kaufman S., Woo S.L.C.,
RA Ledley F.D.;
RT "Structure and expression of human dihydropteridine reductase.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:3329-3333(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-51, AND VARIANTS
RP HPABH4C ASP-23; CYS-150; TYR-158 AND ILE-THR-GLY-218 INS.
RX PubMed=9744478;
RX DOI=10.1002/(SICI)1098-1004(1998)12:4<267::AID-HUMU8>3.3.CO;2-0;
RA Dianzani I., de Sanctis L., Smooker P.M., Gough T.J., Alliaudi C.,
RA Brusco A., Spada M., Blau N., Dobos M., Zhang H.-P., Yang N.,
RA Ponzone A., Armarego W.L.F., Cotton R.G.H.;
RT "Dihydropteridine reductase deficiency: physical structure of the QDPR
RT gene, identification of two new mutations and genotype-phenotype
RT correlations.";
RL Hum. Mutat. 12:267-273(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Hsiao K.-J., Yen P.-F., Lin C.-H., Liu T.-T., Chiang S.-H.,
RA Chen C.-Y., Tsai S.-F.;
RT "The complete sequence of human dihydropteridine reductase gene
RT containing BAC clone 395N09.";
RL Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
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 [10]
RP PROTEIN SEQUENCE OF 2-11 AND 128-138, CLEAVAGE OF INITIATOR
RP METHIONINE, ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Colon carcinoma;
RA Bienvenut W.V., Heiserich L., Gottlieb E.;
RL Submitted (MAR-2008) to UniProtKB.
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RX PubMed=8262916;
RA Su Y., Varughese K.I., Xuong N.H., Bray T.L., Roche D.J.,
RA Whiteley J.M.;
RT "The crystallographic structure of a human dihydropteridine reductase
RT NADH binary complex expressed in Escherichia coli by a cDNA
RT constructed from its rat homologue.";
RL J. Biol. Chem. 268:26836-26841(1993).
RN [15]
RP REVIEW ON VARIANTS.
RX PubMed=7627180; DOI=10.1002/humu.1380050402;
RA Smooker P.M., Cotton R.G.H.;
RT "Molecular basis of dihydropteridine reductase deficiency.";
RL Hum. Mutat. 5:279-284(1995).
RN [16]
RP VARIANTS HPABH4C ASP-23 AND GLY-108.
RX PubMed=8326489;
RA Dianzani I., Howells D.W., Ponzone A., Saleeba J.A., Smooker P.M.,
RA Cotton R.G.H.;
RT "Two new mutations in the dihydropteridine reductase gene in patients
RT with tetrahydrobiopterin deficiency.";
RL J. Med. Genet. 30:465-469(1993).
RN [17]
RP VARIANT HPABH4C THR-123 INS.
RX PubMed=2116088;
RA Howells D.W., Forrest S.M., Dahl H.-H.M., Cotton R.G.H.;
RT "Insertion of an extra codon for threonine is a cause of
RT dihydropteridine reductase deficiency.";
RL Am. J. Hum. Genet. 47:279-285(1990).
RN [18]
RP VARIANTS HPABH4C PRO-14 AND VAL-17.
RX PubMed=10408783;
RX DOI=10.1002/(SICI)1098-1004(1999)13:6<503::AID-HUMU13>3.0.CO;2-F;
RA Smooker P.M., Gough T.J., Cotton R.G.H., Alliaudi C., de Sanctis L.,
RA Dianzani I.;
RT "A series of mutations in the dihydropteridine reductase gene
RT resulting in either abnormal RNA splicing or DHPR protein defects.";
RL Hum. Mutat. 13:503-504(1999).
RN [19]
RP VARIANTS HPABH4C ARG-17; ASP-18; ASP-23; ARG-66; ARG-149 AND CYS-150.
RX PubMed=11153907; DOI=10.1007/s004390000407;
RA Romstad A., Kalkanoglu H.S., Coskun T., Demirkol M., Tokatli A.,
RA Dursun A., Baykal T., Oezalp I., Guldberg P., Guettler F.;
RT "Molecular analysis of 16 Turkish families with DHPR deficiency using
RT denaturing gradient gel electrophoresis (DGGE).";
RL Hum. Genet. 107:546-553(2000).
CC -!- FUNCTION: The product of this enzyme, tetrahydrobiopterin (BH-4),
CC is an essential cofactor for phenylalanine, tyrosine, and
CC tryptophan hydroxylases.
CC -!- CATALYTIC ACTIVITY: A 5,6,7,8-tetrahydropteridine + NAD(P)(+) = a
CC 6,7-dihydropteridine + NAD(P)H.
CC -!- SUBUNIT: Homodimer.
CC -!- DISEASE: Hyperphenylalaninemia, BH4-deficient, C (HPABH4C)
CC [MIM:261630]: Rare autosomal recessive disorder characterized by
CC hyperphenylalaninemia and severe neurologic symptoms (malignant
CC hyperphenylalaninemia) including axial hypotonia and truncal
CC hypertonia, abnormal thermogenesis, and microcephaly. These signs
CC are attributable to depletion of the neurotransmitters dopamine
CC and serotonin, whose syntheses are controlled by tryptophan and
CC tyrosine hydroxylases that use BH-4 as cofactor. Patients do not
CC respond to phenylalanine-restricted diet. HPABH4C is lethal if
CC untreated. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases
CC (SDR) family.
CC -!- WEB RESOURCE: Name=BIOMDB; Note=Db of mutations causing
CC tetrahydrobiopterin deficiencies;
CC URL="http://www.bh4.org/biodef1.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/QDPR";
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DR EMBL; X04882; CAA28571.1; -; mRNA.
DR EMBL; M16447; AAA52305.1; -; mRNA.
DR EMBL; AJ006239; CAA06930.1; -; Genomic_DNA.
DR EMBL; AJ006240; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006241; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006242; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006243; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006244; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006245; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AB053170; BAB20429.1; -; Genomic_DNA.
DR EMBL; AK223437; BAD97157.1; -; mRNA.
DR EMBL; AK289773; BAF82462.1; -; mRNA.
DR EMBL; CH471069; EAW92777.1; -; Genomic_DNA.
DR EMBL; BC000576; AAH00576.1; -; mRNA.
DR PIR; A93655; RDHUP.
DR RefSeq; NP_000311.2; NM_000320.2.
DR UniGene; Hs.75438; -.
DR PDB; 1HDR; X-ray; 2.50 A; A=1-244.
DR PDBsum; 1HDR; -.
DR ProteinModelPortal; P09417; -.
DR SMR; P09417; 9-244.
DR IntAct; P09417; 2.
DR MINT; MINT-5002411; -.
DR STRING; 9606.ENSP00000281243; -.
DR BindingDB; P09417; -.
DR ChEMBL; CHEMBL3730; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P09417; -.
DR DMDM; 118572639; -.
DR REPRODUCTION-2DPAGE; IPI00014439; -.
DR UCD-2DPAGE; P09417; -.
DR PaxDb; P09417; -.
DR PeptideAtlas; P09417; -.
DR PRIDE; P09417; -.
DR DNASU; 5860; -.
DR Ensembl; ENST00000281243; ENSP00000281243; ENSG00000151552.
DR GeneID; 5860; -.
DR KEGG; hsa:5860; -.
DR UCSC; uc003gpd.3; human.
DR CTD; 5860; -.
DR GeneCards; GC04M017488; -.
DR HGNC; HGNC:9752; QDPR.
DR MIM; 261630; phenotype.
DR MIM; 612676; gene.
DR neXtProt; NX_P09417; -.
DR Orphanet; 226; Dihydropteridine reductase deficiency.
DR PharmGKB; PA34094; -.
DR eggNOG; COG1028; -.
DR HOGENOM; HOG000232194; -.
DR HOVERGEN; HBG001000; -.
DR InParanoid; P09417; -.
DR KO; K00357; -.
DR OMA; SDLMWKQ; -.
DR OrthoDB; EOG7060RV; -.
DR PhylomeDB; P09417; -.
DR BioCyc; MetaCyc:HS07746-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P09417; -.
DR ChiTaRS; QDPR; human.
DR EvolutionaryTrace; P09417; -.
DR GeneWiki; QDPR; -.
DR GenomeRNAi; 5860; -.
DR NextBio; 22758; -.
DR PRO; PR:P09417; -.
DR ArrayExpress; P09417; -.
DR Bgee; P09417; -.
DR CleanEx; HS_QDPR; -.
DR Genevestigator; P09417; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0004155; F:6,7-dihydropteridine reductase activity; EXP:Reactome.
DR GO; GO:0009055; F:electron carrier activity; TAS:UniProtKB.
DR GO; GO:0070404; F:NADH binding; IEA:Ensembl.
DR GO; GO:0070402; F:NADPH binding; IEA:Ensembl.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0051066; P:dihydrobiopterin metabolic process; TAS:ProtInc.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; TAS:Reactome.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0010044; P:response to aluminum ion; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR002198; DH_sc/Rdtase_SDR.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR Pfam; PF00106; adh_short; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; Disease mutation; NADP; Oxidoreductase;
KW Phenylketonuria; Polymorphism; Reference proteome;
KW Tetrahydrobiopterin biosynthesis.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 244 Dihydropteridine reductase.
FT /FTId=PRO_0000054636.
FT NP_BIND 14 38 NADP.
FT ACT_SITE 150 150 Proton acceptor.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 14 14 L -> P (in HPABH4C; severe).
FT /FTId=VAR_008121.
FT VARIANT 17 17 G -> R (in HPABH4C; severe).
FT /FTId=VAR_021767.
FT VARIANT 17 17 G -> V (in HPABH4C; severe).
FT /FTId=VAR_008122.
FT VARIANT 18 18 G -> D (in HPABH4C; severe).
FT /FTId=VAR_021768.
FT VARIANT 23 23 G -> D (in HPABH4C; severe).
FT /FTId=VAR_006960.
FT VARIANT 36 36 W -> R (in HPABH4C).
FT /FTId=VAR_006961.
FT VARIANT 51 51 S -> T.
FT /FTId=VAR_013027.
FT VARIANT 66 66 Q -> R (in HPABH4C; severe).
FT /FTId=VAR_021769.
FT VARIANT 74 74 L -> P (in HPABH4C).
FT /FTId=VAR_006962.
FT VARIANT 108 108 W -> G (in HPABH4C).
FT /FTId=VAR_006963.
FT VARIANT 123 123 T -> TT (in HPABH4C).
FT /FTId=VAR_006964.
FT VARIANT 145 145 P -> L (in HPABH4C).
FT /FTId=VAR_006965.
FT VARIANT 149 149 G -> R (in HPABH4C).
FT /FTId=VAR_021770.
FT VARIANT 150 150 Y -> C (in HPABH4C; mild).
FT /FTId=VAR_006966.
FT VARIANT 151 151 G -> S (in HPABH4C; mild).
FT /FTId=VAR_006967.
FT VARIANT 158 158 H -> Y (in HPABH4C; severe).
FT /FTId=VAR_006968.
FT VARIANT 170 170 G -> S (in HPABH4C).
FT /FTId=VAR_006969.
FT VARIANT 212 212 F -> C (in HPABH4C; mild).
FT /FTId=VAR_006970.
FT VARIANT 218 218 G -> GITG (in HPABH4C; mild).
FT /FTId=VAR_006971.
FT STRAND 11 16
FT TURN 17 19
FT HELIX 21 32
FT STRAND 36 43
FT STRAND 48 53
FT HELIX 60 75
FT STRAND 80 85
FT HELIX 100 110
FT HELIX 112 125
FT STRAND 126 135
FT HELIX 138 141
FT HELIX 148 165
FT STRAND 176 181
FT HELIX 188 191
FT HELIX 199 201
FT HELIX 205 216
FT TURN 217 220
FT STRAND 227 233
FT STRAND 236 242
SQ SEQUENCE 244 AA; 25790 MW; 0852F9F0CA38AB1C CRC64;
MAAAAAAGEA RRVLVYGGRG ALGSRCVQAF RARNWWVASV DVVENEEASA SIIVKMTDSF
TEQADQVTAE VGKLLGEEKV DAILCVAGGW AGGNAKSKSL FKNCDLMWKQ SIWTSTISSH
LATKHLKEGG LLTLAGAKAA LDGTPGMIGY GMAKGAVHQL CQSLAGKNSG MPPGAAAIAV
LPVTLDTPMN RKSMPEADFS SWTPLEFLVE TFHDWITGKN RPSSGSLIQV VTTEGRTELT
PAYF
//
ID DHPR_HUMAN Reviewed; 244 AA.
AC P09417; A8K158; Q53F52; Q9H3M5;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 28-NOV-2006, sequence version 2.
DT 22-JAN-2014, entry version 160.
DE RecName: Full=Dihydropteridine reductase;
DE EC=1.5.1.34;
DE AltName: Full=HDHPR;
DE AltName: Full=Quinoid dihydropteridine reductase;
GN Name=QDPR; Synonyms=DHPR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-51.
RX PubMed=3031582; DOI=10.1093/nar/15.5.1921;
RA Dahl H.-H.M., Hutchison W., McAdam W., Wake S., Morgan F.J.,
RA Cotton R.G.H.;
RT "Human dihydropteridine reductase: characterisation of a cDNA clone
RT and its use in analysis of patients with dihydropteridine reductase
RT deficiency.";
RL Nucleic Acids Res. 15:1921-1932(1987).
RN [2]
RP SEQUENCE REVISION TO 51.
RA Dahl H.-H.M.;
RL Submitted (JUL-1987) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-51.
RX PubMed=3033643; DOI=10.1073/pnas.84.10.3329;
RA Lockyer J., Cook R.G., Milstien S., Kaufman S., Woo S.L.C.,
RA Ledley F.D.;
RT "Structure and expression of human dihydropteridine reductase.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:3329-3333(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-51, AND VARIANTS
RP HPABH4C ASP-23; CYS-150; TYR-158 AND ILE-THR-GLY-218 INS.
RX PubMed=9744478;
RX DOI=10.1002/(SICI)1098-1004(1998)12:4<267::AID-HUMU8>3.3.CO;2-0;
RA Dianzani I., de Sanctis L., Smooker P.M., Gough T.J., Alliaudi C.,
RA Brusco A., Spada M., Blau N., Dobos M., Zhang H.-P., Yang N.,
RA Ponzone A., Armarego W.L.F., Cotton R.G.H.;
RT "Dihydropteridine reductase deficiency: physical structure of the QDPR
RT gene, identification of two new mutations and genotype-phenotype
RT correlations.";
RL Hum. Mutat. 12:267-273(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Hsiao K.-J., Yen P.-F., Lin C.-H., Liu T.-T., Chiang S.-H.,
RA Chen C.-Y., Tsai S.-F.;
RT "The complete sequence of human dihydropteridine reductase gene
RT containing BAC clone 395N09.";
RL Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
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 [10]
RP PROTEIN SEQUENCE OF 2-11 AND 128-138, CLEAVAGE OF INITIATOR
RP METHIONINE, ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Colon carcinoma;
RA Bienvenut W.V., Heiserich L., Gottlieb E.;
RL Submitted (MAR-2008) to UniProtKB.
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RX PubMed=8262916;
RA Su Y., Varughese K.I., Xuong N.H., Bray T.L., Roche D.J.,
RA Whiteley J.M.;
RT "The crystallographic structure of a human dihydropteridine reductase
RT NADH binary complex expressed in Escherichia coli by a cDNA
RT constructed from its rat homologue.";
RL J. Biol. Chem. 268:26836-26841(1993).
RN [15]
RP REVIEW ON VARIANTS.
RX PubMed=7627180; DOI=10.1002/humu.1380050402;
RA Smooker P.M., Cotton R.G.H.;
RT "Molecular basis of dihydropteridine reductase deficiency.";
RL Hum. Mutat. 5:279-284(1995).
RN [16]
RP VARIANTS HPABH4C ASP-23 AND GLY-108.
RX PubMed=8326489;
RA Dianzani I., Howells D.W., Ponzone A., Saleeba J.A., Smooker P.M.,
RA Cotton R.G.H.;
RT "Two new mutations in the dihydropteridine reductase gene in patients
RT with tetrahydrobiopterin deficiency.";
RL J. Med. Genet. 30:465-469(1993).
RN [17]
RP VARIANT HPABH4C THR-123 INS.
RX PubMed=2116088;
RA Howells D.W., Forrest S.M., Dahl H.-H.M., Cotton R.G.H.;
RT "Insertion of an extra codon for threonine is a cause of
RT dihydropteridine reductase deficiency.";
RL Am. J. Hum. Genet. 47:279-285(1990).
RN [18]
RP VARIANTS HPABH4C PRO-14 AND VAL-17.
RX PubMed=10408783;
RX DOI=10.1002/(SICI)1098-1004(1999)13:6<503::AID-HUMU13>3.0.CO;2-F;
RA Smooker P.M., Gough T.J., Cotton R.G.H., Alliaudi C., de Sanctis L.,
RA Dianzani I.;
RT "A series of mutations in the dihydropteridine reductase gene
RT resulting in either abnormal RNA splicing or DHPR protein defects.";
RL Hum. Mutat. 13:503-504(1999).
RN [19]
RP VARIANTS HPABH4C ARG-17; ASP-18; ASP-23; ARG-66; ARG-149 AND CYS-150.
RX PubMed=11153907; DOI=10.1007/s004390000407;
RA Romstad A., Kalkanoglu H.S., Coskun T., Demirkol M., Tokatli A.,
RA Dursun A., Baykal T., Oezalp I., Guldberg P., Guettler F.;
RT "Molecular analysis of 16 Turkish families with DHPR deficiency using
RT denaturing gradient gel electrophoresis (DGGE).";
RL Hum. Genet. 107:546-553(2000).
CC -!- FUNCTION: The product of this enzyme, tetrahydrobiopterin (BH-4),
CC is an essential cofactor for phenylalanine, tyrosine, and
CC tryptophan hydroxylases.
CC -!- CATALYTIC ACTIVITY: A 5,6,7,8-tetrahydropteridine + NAD(P)(+) = a
CC 6,7-dihydropteridine + NAD(P)H.
CC -!- SUBUNIT: Homodimer.
CC -!- DISEASE: Hyperphenylalaninemia, BH4-deficient, C (HPABH4C)
CC [MIM:261630]: Rare autosomal recessive disorder characterized by
CC hyperphenylalaninemia and severe neurologic symptoms (malignant
CC hyperphenylalaninemia) including axial hypotonia and truncal
CC hypertonia, abnormal thermogenesis, and microcephaly. These signs
CC are attributable to depletion of the neurotransmitters dopamine
CC and serotonin, whose syntheses are controlled by tryptophan and
CC tyrosine hydroxylases that use BH-4 as cofactor. Patients do not
CC respond to phenylalanine-restricted diet. HPABH4C is lethal if
CC untreated. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases
CC (SDR) family.
CC -!- WEB RESOURCE: Name=BIOMDB; Note=Db of mutations causing
CC tetrahydrobiopterin deficiencies;
CC URL="http://www.bh4.org/biodef1.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/QDPR";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; X04882; CAA28571.1; -; mRNA.
DR EMBL; M16447; AAA52305.1; -; mRNA.
DR EMBL; AJ006239; CAA06930.1; -; Genomic_DNA.
DR EMBL; AJ006240; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006241; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006242; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006243; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006244; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AJ006245; CAA06930.1; JOINED; Genomic_DNA.
DR EMBL; AB053170; BAB20429.1; -; Genomic_DNA.
DR EMBL; AK223437; BAD97157.1; -; mRNA.
DR EMBL; AK289773; BAF82462.1; -; mRNA.
DR EMBL; CH471069; EAW92777.1; -; Genomic_DNA.
DR EMBL; BC000576; AAH00576.1; -; mRNA.
DR PIR; A93655; RDHUP.
DR RefSeq; NP_000311.2; NM_000320.2.
DR UniGene; Hs.75438; -.
DR PDB; 1HDR; X-ray; 2.50 A; A=1-244.
DR PDBsum; 1HDR; -.
DR ProteinModelPortal; P09417; -.
DR SMR; P09417; 9-244.
DR IntAct; P09417; 2.
DR MINT; MINT-5002411; -.
DR STRING; 9606.ENSP00000281243; -.
DR BindingDB; P09417; -.
DR ChEMBL; CHEMBL3730; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P09417; -.
DR DMDM; 118572639; -.
DR REPRODUCTION-2DPAGE; IPI00014439; -.
DR UCD-2DPAGE; P09417; -.
DR PaxDb; P09417; -.
DR PeptideAtlas; P09417; -.
DR PRIDE; P09417; -.
DR DNASU; 5860; -.
DR Ensembl; ENST00000281243; ENSP00000281243; ENSG00000151552.
DR GeneID; 5860; -.
DR KEGG; hsa:5860; -.
DR UCSC; uc003gpd.3; human.
DR CTD; 5860; -.
DR GeneCards; GC04M017488; -.
DR HGNC; HGNC:9752; QDPR.
DR MIM; 261630; phenotype.
DR MIM; 612676; gene.
DR neXtProt; NX_P09417; -.
DR Orphanet; 226; Dihydropteridine reductase deficiency.
DR PharmGKB; PA34094; -.
DR eggNOG; COG1028; -.
DR HOGENOM; HOG000232194; -.
DR HOVERGEN; HBG001000; -.
DR InParanoid; P09417; -.
DR KO; K00357; -.
DR OMA; SDLMWKQ; -.
DR OrthoDB; EOG7060RV; -.
DR PhylomeDB; P09417; -.
DR BioCyc; MetaCyc:HS07746-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P09417; -.
DR ChiTaRS; QDPR; human.
DR EvolutionaryTrace; P09417; -.
DR GeneWiki; QDPR; -.
DR GenomeRNAi; 5860; -.
DR NextBio; 22758; -.
DR PRO; PR:P09417; -.
DR ArrayExpress; P09417; -.
DR Bgee; P09417; -.
DR CleanEx; HS_QDPR; -.
DR Genevestigator; P09417; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0004155; F:6,7-dihydropteridine reductase activity; EXP:Reactome.
DR GO; GO:0009055; F:electron carrier activity; TAS:UniProtKB.
DR GO; GO:0070404; F:NADH binding; IEA:Ensembl.
DR GO; GO:0070402; F:NADPH binding; IEA:Ensembl.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0051066; P:dihydrobiopterin metabolic process; TAS:ProtInc.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; TAS:Reactome.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0010044; P:response to aluminum ion; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR002198; DH_sc/Rdtase_SDR.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR Pfam; PF00106; adh_short; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; Disease mutation; NADP; Oxidoreductase;
KW Phenylketonuria; Polymorphism; Reference proteome;
KW Tetrahydrobiopterin biosynthesis.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 244 Dihydropteridine reductase.
FT /FTId=PRO_0000054636.
FT NP_BIND 14 38 NADP.
FT ACT_SITE 150 150 Proton acceptor.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 14 14 L -> P (in HPABH4C; severe).
FT /FTId=VAR_008121.
FT VARIANT 17 17 G -> R (in HPABH4C; severe).
FT /FTId=VAR_021767.
FT VARIANT 17 17 G -> V (in HPABH4C; severe).
FT /FTId=VAR_008122.
FT VARIANT 18 18 G -> D (in HPABH4C; severe).
FT /FTId=VAR_021768.
FT VARIANT 23 23 G -> D (in HPABH4C; severe).
FT /FTId=VAR_006960.
FT VARIANT 36 36 W -> R (in HPABH4C).
FT /FTId=VAR_006961.
FT VARIANT 51 51 S -> T.
FT /FTId=VAR_013027.
FT VARIANT 66 66 Q -> R (in HPABH4C; severe).
FT /FTId=VAR_021769.
FT VARIANT 74 74 L -> P (in HPABH4C).
FT /FTId=VAR_006962.
FT VARIANT 108 108 W -> G (in HPABH4C).
FT /FTId=VAR_006963.
FT VARIANT 123 123 T -> TT (in HPABH4C).
FT /FTId=VAR_006964.
FT VARIANT 145 145 P -> L (in HPABH4C).
FT /FTId=VAR_006965.
FT VARIANT 149 149 G -> R (in HPABH4C).
FT /FTId=VAR_021770.
FT VARIANT 150 150 Y -> C (in HPABH4C; mild).
FT /FTId=VAR_006966.
FT VARIANT 151 151 G -> S (in HPABH4C; mild).
FT /FTId=VAR_006967.
FT VARIANT 158 158 H -> Y (in HPABH4C; severe).
FT /FTId=VAR_006968.
FT VARIANT 170 170 G -> S (in HPABH4C).
FT /FTId=VAR_006969.
FT VARIANT 212 212 F -> C (in HPABH4C; mild).
FT /FTId=VAR_006970.
FT VARIANT 218 218 G -> GITG (in HPABH4C; mild).
FT /FTId=VAR_006971.
FT STRAND 11 16
FT TURN 17 19
FT HELIX 21 32
FT STRAND 36 43
FT STRAND 48 53
FT HELIX 60 75
FT STRAND 80 85
FT HELIX 100 110
FT HELIX 112 125
FT STRAND 126 135
FT HELIX 138 141
FT HELIX 148 165
FT STRAND 176 181
FT HELIX 188 191
FT HELIX 199 201
FT HELIX 205 216
FT TURN 217 220
FT STRAND 227 233
FT STRAND 236 242
SQ SEQUENCE 244 AA; 25790 MW; 0852F9F0CA38AB1C CRC64;
MAAAAAAGEA RRVLVYGGRG ALGSRCVQAF RARNWWVASV DVVENEEASA SIIVKMTDSF
TEQADQVTAE VGKLLGEEKV DAILCVAGGW AGGNAKSKSL FKNCDLMWKQ SIWTSTISSH
LATKHLKEGG LLTLAGAKAA LDGTPGMIGY GMAKGAVHQL CQSLAGKNSG MPPGAAAIAV
LPVTLDTPMN RKSMPEADFS SWTPLEFLVE TFHDWITGKN RPSSGSLIQV VTTEGRTELT
PAYF
//
MIM
261630
*RECORD*
*FIELD* NO
261630
*FIELD* TI
#261630 HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C; HPABH4C
;;HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO DHPR
read moreDEFICIENCY;;
DIHYDROPTERIDINE REDUCTASE DEFICIENCY;;
DHPR DEFICIENCY;;
QUINOID DIHYDROPTERIDINE REDUCTASE DEFICIENCY;;
QDPR DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because tetrahydrobiopterin
(BH4)-deficient hyperphenylalaninemia (HPA) due to dihydropteridine
reductase deficiency (HPABH4C) is caused by mutation in the QDPR gene
(612676), which encodes an enzyme involved in the salvage pathway for
BH4.
For a general phenotypic description and a discussion of genetic
heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A
(261640).
CLINICAL FEATURES
Smith et al. (1975) described 3 children, 2 of them sibs, with an
unusual type of phenylketonuria. All 3 (2 of them observed from the
neonatal period) had a progressive neurologic illness that did not
respond to a low phenylalanine diet, unlike classic PKU (261600). The
biochemical features suggested that the block in conversion of
phenylalanine to tyrosine was less severe than in classic PKU.
Phenylalanine hydroxylase (PAH; 612349), measured in 1 patient, was
normal. Smith et al. (1975) suggested that the patients had a disorder
of biopterin metabolism possibly due to a defect in the enzyme
dihydropteridine reductase.
Butler et al. (1975) reported dihydropteridine reductase deficiency in a
patient unresponsive to dietary treatment. Biopterin is the natural
cofactor for phenylalanine hydroxylase. In its active tetra-hydro form
(BH4), biopterin donates hydrogen ions during the hydroxylation
reaction. The same cofactor system is active in neural tissue for
hydroxylation of tyrosine to dihydroxyphenylalanine (levodopa) in the
synthesis of amine transmitters (dipaminine, noradrenaline, and
adrenaline) and serotonin. Phenylalanine restriction would not be
expected to help the neurologic problem. Basal ganglion symptoms can be
related to the importance of levodopa and dopamine to that part of the
brain.
Kaufman et al. (1975) demonstrated absence of dihydropteridine reductase
in liver, brain, and cultured skin fibroblasts of a patient with
elevated blood phenylalanine and no response to diet despite good
control of blood levels.
Watts et al. (1979) reported a patient with hyperphenylalaninemia who
had better tolerance of phenylalanine compared to patients with classic
PKU. However, unlike patients with classic PKU, treatment with
trimethoprim reduced the phenylalanine tolerance in this patient. Since
trimethoprim inhibits 7,8-dihydrobiopterin reduction, Watts et al.
(1979) speculated that the causative defect may involve the gene for
dihydropteridine reductase such that it is sensitive to the reduced
availability of tetrahydrobiopterin produced by trimethoprim.
Woody et al. (1989) pointed out that without folinic acid therapy as a
source of tetrahydrofolate, patients with DHPR deficiency show
progressive basal ganglia and other subcortical calcification. The
pattern of calcification resembled that seen in CNS folate deficiency,
both that in the congenital form (229050) and that in the
methotrexate-induced form.
Larnaout et al. (1998) described 2 brothers with juvenile-onset DHPR
deficiency. Both were considered normal until 6 years of age when they
developed a fluctuating and progressive encephalopathy combining mental
retardation, epilepsy, and pyramidal, cerebellar, and extrapyramidal
signs.
DIAGNOSIS
- Prenatal Diagnosis
Dahl et al. (1987, 1988) showed that RFLPs of the DHPR locus could be
used for prenatal diagnosis.
CLINICAL MANAGEMENT
Danks et al. (1975) found that intravenous tetrahydrobiopterin (BH4)
treatment was effective and resulted in a fall in serum phenylalanine.
Oral therapy had no effect.
MOLECULAR GENETICS
In a patient with dihydropteridine reductase deficiency, the offspring
of consanguineous parents, Howells et al. (1990) identified homozygosity
for a mutation in the QDPR gene (612676.0001).
Smooker and Cotton (1995) reviewed 12 point mutations that had been
described in DHPR cDNA, all of which resulted in dihydropteridine
reductase deficiency. The mutations resulted in amino acid
substitutions, insertions, or premature terminations. A further 2
mutations resulted in aberrant splicing of QDPR transcripts.
Romstad et al. (2000) studied 17 patients belonging to 16 Turkish
families with DHPR deficiency. The patients were detected at neonatal
screening for hyperphenylalaninemia or upon the development of
neurologic symptoms. A mutation screen of the entire open reading frame
and all splice sites of the QDPR gene identified 10 different mutations,
7 of which were novel (e.g., 612676.0007). Six of the mutations were
missense, 2 were nonsense, and 2 were frameshift mutations. All patients
had homoallelic genotypes, which allowed the establishment of
genotype-phenotype associations.
*FIELD* SA
Danks et al. (1978); Danks et al. (1979); Dianzani et al. (1998);
Firgaira et al. (1980); Firgaira et al. (1979); Grobe et al. (1978);
Longhi et al. (1985); Milstien et al. (1976); Milstien et al. (1980)
*FIELD* RF
1. Butler, I. J.; Holtzman, N. A.; Kaufman, S.; Koslow, S. H.; Krumholz,
A.; Milstien, S.: Phenylketonuria due to deficiency of dihydropteridine
reductase. (Abstract) Pediat. Res. 9: 348, 1975.
2. Dahl, H.-H. M.; Hutchinson, W.; McAdam, W.; Wake, S.; Morgan, F.
J.; Cotton, R. G. H.: Human dihydropteridine reductase: characterisation
of a cDNA clone and its use in analysis of patients with dihydropteridine
reductase deficiency. Nucleic Acids Res. 15: 1921-1932, 1987.
3. Dahl, H.-H. M.; Wake, S.; Cotton, R. G. H.; Danks, D. M.: The
use of restriction fragment length polymorphisms in prenatal diagnosis
of dihydropteridine reductase deficiency. J. Med. Genet. 25: 25-28,
1988.
4. Danks, D. M.; Bartholome, K.; Clayton, B. E.; Curtius, H.; Grobe,
H.; Lemming, R.; Pfleiderer, W.; Rembold, H.; Rey, F.: Malignant
hyperphenylalaninaemia--current status (June 1977). J. Inherit. Metab.
Dis. 1: 49-53, 1978.
5. Danks, D. M.; Cotton, R. G. H.; Schlesinger, P.: Tetrahydrobiopterin
treatment of variant form of phenylketonuria. (Letter) Lancet 306:
1043 only, 1975. Note: Originally Volume II.
6. Danks, D. M.; Schlesinger, P.; Firgaira, F.; Cotton, R. G. H.;
Watson, B. M.; Rembold, H.; Hennings, G.: Malignant hyperphenylalaninemia--clinical
features, biochemical findings, and experience with administration
of biopterins. Pediat. Res. 13: 1150-1155, 1979.
7. Dianzani, I.; de Sanctis, L.; Smooker, P. M.; Gough, T. J.; Alliaudi,
C.; Brusco, A.; Spada, M.; Blau, N.; Dobos, M.; Zhang, H.-P.; Yang,
N.; Ponzone, A.; Armarego, W. L. F.; Cotton, R. G. H.: Dihydropteridine
reductase deficiency: physical structure of the QDPR gene, identification
of two new mutations and genotype-phenotype correlations. Hum. Mutat. 12:
267-273, 1998.
8. Firgaira, F. A.; Cotton, R. G. H.; Danks, D. M.: Dihydropteridine
reductase deficiency: diagnosis by assay on peripheral blood cells.
(Letter) Lancet 315: 160 only, 1980. Note: Originally Volume I.
9. Firgaira, F. A.; Cotton, R. G. H.; Danks, D. M.: Dihydropteridine
reductase deficiency: diagnosis by assays on peripheral blood-cells. Lancet 314:
1260-1263, 1979. Note: Originally Volume II.
10. Grobe, H.; Bartholome, K.; Milstien, S.; Kaufman, S.: Hyperphenylalaninaemia
due to dihydropteridine reductase deficiency. Europ. J. Pediat. 129:
93-98, 1978.
11. Howells, D. W.; Forrest, S. M.; Dahl, H.-H. M.; Cotton, R. G.
H.: Insertion of an extra codon for threonine is a cause of dihydropteridine
reductase deficiency. Am. J. Hum. Genet. 47: 279-285, 1990.
12. Kaufman, S.; Holtzman, N. A.; Milstien, S.; Butler, I. J.; Krumholz,
A.: Phenylketonuria due to a deficiency of dihydropteridine reductase. New
Eng. J. Med. 293: 785-790, 1975.
13. Larnaout, A.; Belal, S.; Miladi, N.; Kaabachi, N.; Mebazza, A.;
Dhondt, J. L.; Hentati, F.: Juvenile form of dihydropteridine reductase
deficiency in 2 Tunisian patients. Neuropediatrics 29: 322-323,
1998.
14. Longhi, R.; Riva, E.; Valsasina, R.; Paccanelli, S.; Giovannini,
M.: Phenylketonuria due to dihydropteridine reductase deficiency:
presentation of two cases. J. Inherit. Metab. Dis. 8 (suppl. 2):
97-98, 1985.
15. Milstien, S.; Holtzman, N. A.; O'Flynn, M. E.; Thomas, G. H.;
Butler, I. J.; Kaufman, S.: Hyperphenylalaninemia due to dihydropteridine
reductase deficiency: assay of the enzyme in fibroblasts from affected
infants, heterozygotes, and in normal amniotic fluid cells. J. Pediat. 89:
763-766, 1976.
16. Milstien, S.; Kaufman, S.; Summer, G. K.: Hyperphenylalaninemia
due to dihydropteridine reductase deficiency: diagnosed by measurement
of oxidized and reduced pterins in urine. Pediatrics 65: 806-810,
1980.
17. Romstad, A.; Kalkanoglu, H. S.; Coskun, T.; Demirkol, M.; Tokatli,
A.; Dursun, A.; Baykal, T.; Ozalp, I.; Guldberg, P.; Guttler, F.:
Molecular analysis of 16 Turkish families with DHPR deficiency using
denaturing gradient gel electrophoresis (DGGE). Hum. Genet. 107:
546-553, 2000.
18. Smith, I.; Clayton, B. E.; Wolff, O. H.: New variant of phenylketonuria
with progressive neurological illness unresponsive to phenylalanine
restriction. Lancet 305: 1108-1111, 1975. Note: Originally Volume
I.
19. Smooker, P. M.; Cotton, R. G. H.: Molecular basis of dihydropteridine
reductase deficiency. Hum. Mutat. 5: 279-284, 1995.
20. Watts, R. W. E.; Purkiss, P.; Chalmers, R. A.: A new variant
form of phenylketonuria. Quart. J. Med. 48: 403-417, 1979.
21. Woody, R. C.; Brewster, M. A.; Glasier, C.: Progressive intracranial
calcification in dihydropteridine reductase deficiency prior to folinic
acid therapy. Neurology 39: 673-675, 1989.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor feeding in infancy
HEAD AND NECK:
[Head];
Microcephaly;
[Mouth];
Hypersalivation
ABDOMEN:
[Gastrointestinal];
Swallowing difficulties
NEUROLOGIC:
[Central nervous system];
Delayed development;
Psychomotor retardation;
Mental retardation;
Hypotonia, truncal;
Hypertonia of the extremities;
Uncoordinated movements;
Tremor;
Dystonia;
Seizures;
Choreoathetosis;
Intracerebral calcifications;
[Behavioral/psychiatric manifestations];
Irritability
METABOLIC FEATURES:
Hyperthermia, episodic
LABORATORY ABNORMALITIES:
Hyperphenylalaninemia;
Decreased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA)
in CSF;
Increased biopterin in urine and CSF;
Decreased or absent dihydropteridine reductase activity
MISCELLANEOUS:
Onset in infancy;
Variable severity;
Progressive neurologic deterioration if untreated;
Diurnal fluctuation of neurologic symptoms;
Defect in tetrahydrobiopterin (BH4) synthesis;
Treatment with BH4 is effective;
Neurotransmitter treatment with L-dopa and serotonin or precursors
is effective;
Early treatment can reduce neurologic symptoms
MOLECULAR BASIS:
Caused by mutation in the quinoid dihydropteridine reductase gene
(QDPR, 612676.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 4/10/2009
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 01/05/2010
ckniffin: 4/10/2009
*FIELD* CN
Cassandra L. Kniffin - updated: 4/10/2009
Victor A. McKusick - updated: 12/18/2000
Victor A. McKusick - updated: 7/14/1999
Victor A. McKusick - updated: 6/2/1999
Victor A. McKusick - updated: 9/18/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 04/15/2009
ckniffin: 4/10/2009
carol: 4/1/2009
carol: 3/24/2009
terry: 3/24/2009
terry: 3/20/2009
carol: 3/19/2009
terry: 3/13/2009
terry: 6/9/2005
alopez: 3/17/2004
mcapotos: 1/18/2001
mcapotos: 1/4/2001
terry: 12/18/2000
alopez: 11/24/1999
jlewis: 8/3/1999
jlewis: 7/30/1999
terry: 7/14/1999
carol: 6/15/1999
jlewis: 6/15/1999
jlewis: 6/14/1999
terry: 6/2/1999
carol: 9/23/1998
dkim: 9/23/1998
terry: 9/18/1998
mark: 10/14/1997
terry: 10/7/1997
mark: 1/22/1996
mark: 1/19/1996
mark: 7/6/1995
davew: 8/19/1994
mimadm: 4/14/1994
warfield: 3/9/1994
carol: 9/27/1993
supermim: 3/17/1992
*RECORD*
*FIELD* NO
261630
*FIELD* TI
#261630 HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C; HPABH4C
;;HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO DHPR
read moreDEFICIENCY;;
DIHYDROPTERIDINE REDUCTASE DEFICIENCY;;
DHPR DEFICIENCY;;
QUINOID DIHYDROPTERIDINE REDUCTASE DEFICIENCY;;
QDPR DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because tetrahydrobiopterin
(BH4)-deficient hyperphenylalaninemia (HPA) due to dihydropteridine
reductase deficiency (HPABH4C) is caused by mutation in the QDPR gene
(612676), which encodes an enzyme involved in the salvage pathway for
BH4.
For a general phenotypic description and a discussion of genetic
heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A
(261640).
CLINICAL FEATURES
Smith et al. (1975) described 3 children, 2 of them sibs, with an
unusual type of phenylketonuria. All 3 (2 of them observed from the
neonatal period) had a progressive neurologic illness that did not
respond to a low phenylalanine diet, unlike classic PKU (261600). The
biochemical features suggested that the block in conversion of
phenylalanine to tyrosine was less severe than in classic PKU.
Phenylalanine hydroxylase (PAH; 612349), measured in 1 patient, was
normal. Smith et al. (1975) suggested that the patients had a disorder
of biopterin metabolism possibly due to a defect in the enzyme
dihydropteridine reductase.
Butler et al. (1975) reported dihydropteridine reductase deficiency in a
patient unresponsive to dietary treatment. Biopterin is the natural
cofactor for phenylalanine hydroxylase. In its active tetra-hydro form
(BH4), biopterin donates hydrogen ions during the hydroxylation
reaction. The same cofactor system is active in neural tissue for
hydroxylation of tyrosine to dihydroxyphenylalanine (levodopa) in the
synthesis of amine transmitters (dipaminine, noradrenaline, and
adrenaline) and serotonin. Phenylalanine restriction would not be
expected to help the neurologic problem. Basal ganglion symptoms can be
related to the importance of levodopa and dopamine to that part of the
brain.
Kaufman et al. (1975) demonstrated absence of dihydropteridine reductase
in liver, brain, and cultured skin fibroblasts of a patient with
elevated blood phenylalanine and no response to diet despite good
control of blood levels.
Watts et al. (1979) reported a patient with hyperphenylalaninemia who
had better tolerance of phenylalanine compared to patients with classic
PKU. However, unlike patients with classic PKU, treatment with
trimethoprim reduced the phenylalanine tolerance in this patient. Since
trimethoprim inhibits 7,8-dihydrobiopterin reduction, Watts et al.
(1979) speculated that the causative defect may involve the gene for
dihydropteridine reductase such that it is sensitive to the reduced
availability of tetrahydrobiopterin produced by trimethoprim.
Woody et al. (1989) pointed out that without folinic acid therapy as a
source of tetrahydrofolate, patients with DHPR deficiency show
progressive basal ganglia and other subcortical calcification. The
pattern of calcification resembled that seen in CNS folate deficiency,
both that in the congenital form (229050) and that in the
methotrexate-induced form.
Larnaout et al. (1998) described 2 brothers with juvenile-onset DHPR
deficiency. Both were considered normal until 6 years of age when they
developed a fluctuating and progressive encephalopathy combining mental
retardation, epilepsy, and pyramidal, cerebellar, and extrapyramidal
signs.
DIAGNOSIS
- Prenatal Diagnosis
Dahl et al. (1987, 1988) showed that RFLPs of the DHPR locus could be
used for prenatal diagnosis.
CLINICAL MANAGEMENT
Danks et al. (1975) found that intravenous tetrahydrobiopterin (BH4)
treatment was effective and resulted in a fall in serum phenylalanine.
Oral therapy had no effect.
MOLECULAR GENETICS
In a patient with dihydropteridine reductase deficiency, the offspring
of consanguineous parents, Howells et al. (1990) identified homozygosity
for a mutation in the QDPR gene (612676.0001).
Smooker and Cotton (1995) reviewed 12 point mutations that had been
described in DHPR cDNA, all of which resulted in dihydropteridine
reductase deficiency. The mutations resulted in amino acid
substitutions, insertions, or premature terminations. A further 2
mutations resulted in aberrant splicing of QDPR transcripts.
Romstad et al. (2000) studied 17 patients belonging to 16 Turkish
families with DHPR deficiency. The patients were detected at neonatal
screening for hyperphenylalaninemia or upon the development of
neurologic symptoms. A mutation screen of the entire open reading frame
and all splice sites of the QDPR gene identified 10 different mutations,
7 of which were novel (e.g., 612676.0007). Six of the mutations were
missense, 2 were nonsense, and 2 were frameshift mutations. All patients
had homoallelic genotypes, which allowed the establishment of
genotype-phenotype associations.
*FIELD* SA
Danks et al. (1978); Danks et al. (1979); Dianzani et al. (1998);
Firgaira et al. (1980); Firgaira et al. (1979); Grobe et al. (1978);
Longhi et al. (1985); Milstien et al. (1976); Milstien et al. (1980)
*FIELD* RF
1. Butler, I. J.; Holtzman, N. A.; Kaufman, S.; Koslow, S. H.; Krumholz,
A.; Milstien, S.: Phenylketonuria due to deficiency of dihydropteridine
reductase. (Abstract) Pediat. Res. 9: 348, 1975.
2. Dahl, H.-H. M.; Hutchinson, W.; McAdam, W.; Wake, S.; Morgan, F.
J.; Cotton, R. G. H.: Human dihydropteridine reductase: characterisation
of a cDNA clone and its use in analysis of patients with dihydropteridine
reductase deficiency. Nucleic Acids Res. 15: 1921-1932, 1987.
3. Dahl, H.-H. M.; Wake, S.; Cotton, R. G. H.; Danks, D. M.: The
use of restriction fragment length polymorphisms in prenatal diagnosis
of dihydropteridine reductase deficiency. J. Med. Genet. 25: 25-28,
1988.
4. Danks, D. M.; Bartholome, K.; Clayton, B. E.; Curtius, H.; Grobe,
H.; Lemming, R.; Pfleiderer, W.; Rembold, H.; Rey, F.: Malignant
hyperphenylalaninaemia--current status (June 1977). J. Inherit. Metab.
Dis. 1: 49-53, 1978.
5. Danks, D. M.; Cotton, R. G. H.; Schlesinger, P.: Tetrahydrobiopterin
treatment of variant form of phenylketonuria. (Letter) Lancet 306:
1043 only, 1975. Note: Originally Volume II.
6. Danks, D. M.; Schlesinger, P.; Firgaira, F.; Cotton, R. G. H.;
Watson, B. M.; Rembold, H.; Hennings, G.: Malignant hyperphenylalaninemia--clinical
features, biochemical findings, and experience with administration
of biopterins. Pediat. Res. 13: 1150-1155, 1979.
7. Dianzani, I.; de Sanctis, L.; Smooker, P. M.; Gough, T. J.; Alliaudi,
C.; Brusco, A.; Spada, M.; Blau, N.; Dobos, M.; Zhang, H.-P.; Yang,
N.; Ponzone, A.; Armarego, W. L. F.; Cotton, R. G. H.: Dihydropteridine
reductase deficiency: physical structure of the QDPR gene, identification
of two new mutations and genotype-phenotype correlations. Hum. Mutat. 12:
267-273, 1998.
8. Firgaira, F. A.; Cotton, R. G. H.; Danks, D. M.: Dihydropteridine
reductase deficiency: diagnosis by assay on peripheral blood cells.
(Letter) Lancet 315: 160 only, 1980. Note: Originally Volume I.
9. Firgaira, F. A.; Cotton, R. G. H.; Danks, D. M.: Dihydropteridine
reductase deficiency: diagnosis by assays on peripheral blood-cells. Lancet 314:
1260-1263, 1979. Note: Originally Volume II.
10. Grobe, H.; Bartholome, K.; Milstien, S.; Kaufman, S.: Hyperphenylalaninaemia
due to dihydropteridine reductase deficiency. Europ. J. Pediat. 129:
93-98, 1978.
11. Howells, D. W.; Forrest, S. M.; Dahl, H.-H. M.; Cotton, R. G.
H.: Insertion of an extra codon for threonine is a cause of dihydropteridine
reductase deficiency. Am. J. Hum. Genet. 47: 279-285, 1990.
12. Kaufman, S.; Holtzman, N. A.; Milstien, S.; Butler, I. J.; Krumholz,
A.: Phenylketonuria due to a deficiency of dihydropteridine reductase. New
Eng. J. Med. 293: 785-790, 1975.
13. Larnaout, A.; Belal, S.; Miladi, N.; Kaabachi, N.; Mebazza, A.;
Dhondt, J. L.; Hentati, F.: Juvenile form of dihydropteridine reductase
deficiency in 2 Tunisian patients. Neuropediatrics 29: 322-323,
1998.
14. Longhi, R.; Riva, E.; Valsasina, R.; Paccanelli, S.; Giovannini,
M.: Phenylketonuria due to dihydropteridine reductase deficiency:
presentation of two cases. J. Inherit. Metab. Dis. 8 (suppl. 2):
97-98, 1985.
15. Milstien, S.; Holtzman, N. A.; O'Flynn, M. E.; Thomas, G. H.;
Butler, I. J.; Kaufman, S.: Hyperphenylalaninemia due to dihydropteridine
reductase deficiency: assay of the enzyme in fibroblasts from affected
infants, heterozygotes, and in normal amniotic fluid cells. J. Pediat. 89:
763-766, 1976.
16. Milstien, S.; Kaufman, S.; Summer, G. K.: Hyperphenylalaninemia
due to dihydropteridine reductase deficiency: diagnosed by measurement
of oxidized and reduced pterins in urine. Pediatrics 65: 806-810,
1980.
17. Romstad, A.; Kalkanoglu, H. S.; Coskun, T.; Demirkol, M.; Tokatli,
A.; Dursun, A.; Baykal, T.; Ozalp, I.; Guldberg, P.; Guttler, F.:
Molecular analysis of 16 Turkish families with DHPR deficiency using
denaturing gradient gel electrophoresis (DGGE). Hum. Genet. 107:
546-553, 2000.
18. Smith, I.; Clayton, B. E.; Wolff, O. H.: New variant of phenylketonuria
with progressive neurological illness unresponsive to phenylalanine
restriction. Lancet 305: 1108-1111, 1975. Note: Originally Volume
I.
19. Smooker, P. M.; Cotton, R. G. H.: Molecular basis of dihydropteridine
reductase deficiency. Hum. Mutat. 5: 279-284, 1995.
20. Watts, R. W. E.; Purkiss, P.; Chalmers, R. A.: A new variant
form of phenylketonuria. Quart. J. Med. 48: 403-417, 1979.
21. Woody, R. C.; Brewster, M. A.; Glasier, C.: Progressive intracranial
calcification in dihydropteridine reductase deficiency prior to folinic
acid therapy. Neurology 39: 673-675, 1989.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor feeding in infancy
HEAD AND NECK:
[Head];
Microcephaly;
[Mouth];
Hypersalivation
ABDOMEN:
[Gastrointestinal];
Swallowing difficulties
NEUROLOGIC:
[Central nervous system];
Delayed development;
Psychomotor retardation;
Mental retardation;
Hypotonia, truncal;
Hypertonia of the extremities;
Uncoordinated movements;
Tremor;
Dystonia;
Seizures;
Choreoathetosis;
Intracerebral calcifications;
[Behavioral/psychiatric manifestations];
Irritability
METABOLIC FEATURES:
Hyperthermia, episodic
LABORATORY ABNORMALITIES:
Hyperphenylalaninemia;
Decreased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA)
in CSF;
Increased biopterin in urine and CSF;
Decreased or absent dihydropteridine reductase activity
MISCELLANEOUS:
Onset in infancy;
Variable severity;
Progressive neurologic deterioration if untreated;
Diurnal fluctuation of neurologic symptoms;
Defect in tetrahydrobiopterin (BH4) synthesis;
Treatment with BH4 is effective;
Neurotransmitter treatment with L-dopa and serotonin or precursors
is effective;
Early treatment can reduce neurologic symptoms
MOLECULAR BASIS:
Caused by mutation in the quinoid dihydropteridine reductase gene
(QDPR, 612676.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 4/10/2009
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 01/05/2010
ckniffin: 4/10/2009
*FIELD* CN
Cassandra L. Kniffin - updated: 4/10/2009
Victor A. McKusick - updated: 12/18/2000
Victor A. McKusick - updated: 7/14/1999
Victor A. McKusick - updated: 6/2/1999
Victor A. McKusick - updated: 9/18/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 04/15/2009
ckniffin: 4/10/2009
carol: 4/1/2009
carol: 3/24/2009
terry: 3/24/2009
terry: 3/20/2009
carol: 3/19/2009
terry: 3/13/2009
terry: 6/9/2005
alopez: 3/17/2004
mcapotos: 1/18/2001
mcapotos: 1/4/2001
terry: 12/18/2000
alopez: 11/24/1999
jlewis: 8/3/1999
jlewis: 7/30/1999
terry: 7/14/1999
carol: 6/15/1999
jlewis: 6/15/1999
jlewis: 6/14/1999
terry: 6/2/1999
carol: 9/23/1998
dkim: 9/23/1998
terry: 9/18/1998
mark: 10/14/1997
terry: 10/7/1997
mark: 1/22/1996
mark: 1/19/1996
mark: 7/6/1995
davew: 8/19/1994
mimadm: 4/14/1994
warfield: 3/9/1994
carol: 9/27/1993
supermim: 3/17/1992
MIM
612676
*RECORD*
*FIELD* NO
612676
*FIELD* TI
*612676 QUINOID DIHYDROPTERIDINE REDUCTASE; QDPR
;;DIHYDROPTERIDINE REDUCTASE; DHPR
read more*FIELD* TX
DESCRIPTION
Dihydropteridine reductase (EC 1.6.99.7) catalyzes the NADH-mediated
reduction of quinonoid dihydrobiopterin and is an essential component of
the pterin-dependent aromatic amino acid hydroxylating systems (Lockyer
et al., 1987).
CLONING
Dahl et al. (1987) and Lockyer et al. (1987) isolated a cDNA clone for
DHPR that spans the complete coding region and presented the nucleotide
sequence and predicted amino acid sequence of the protein. They found
that the 244-amino acid DHPR protein does not share extensive homology
with the enzymatically related protein dihydrofolate reductase (DHFR;
126060).
MAPPING
By study of mouse-human somatic cell hybrids, Kuhl et al. (1979) mapped
the structural gene for quinoid dihydropteridine reductase on chromosome
4.
MacDonald et al. (1987) used a portion of a cDNA clone corresponding to
the 3-prime end of the human QDPR mRNA as a probe to map that gene by
analysis of somatic cell hybrid lines. The regional localization
achieved was 4p16.1-p15.1. With the use of a RFLP demonstrated by the
probe, they showed only loose linkage of the gene to D4S10, the marker
of Huntington disease (143100). Thus, QDPR was excluded as a candidate
gene in HD.
Brown and Dahl (1987) reported the localization of the DHPR gene to
4p15.3 by in situ hybridization using a cDNA probe.
On the basis of 2 cases of dihydropteridine reductase deficiency
(261630) with overlapping deletions of 4p, Sumi et al. (1990) concluded
that the DHPR gene is probably located on 4p15.31.
MOLECULAR GENETICS
In a patient with BH4-deficient hyperphenylalaninemia due to
dihydropteridine reductase deficiency (HPABH4C; 261630), the offspring
of consanguineous parents, Howells et al. (1990) identified homozygosity
for a mutation in the QDPR gene (612676.0001).
Smooker and Cotton (1995) reviewed 12 point mutations that had been
described in DHPR cDNA, all of which resulted in dihydropteridine
reductase deficiency. The mutations resulted in amino acid
substitutions, insertions, or premature terminations. A further 2
mutations resulted in aberrant splicing of QDPR transcripts.
Romstad et al. (2000) studied 17 patients belonging to 16 Turkish
families with DHPR deficiency. The patients were detected at neonatal
screening for hyperphenylalaninemia or upon the development of
neurologic symptoms. A mutation screen of the entire open reading frame
and all splice sites of the QDPR gene identified 10 different mutations,
7 of which were novel (e.g., 612676.0007). Six of the mutations were
missense, 2 were nonsense, and 2 were frameshift mutations. All patients
had homoallelic genotypes, which allowed the establishment of
genotype-phenotype associations.
*FIELD* AV
.0001
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, 3-BP INS, 390ACT
Howells et al. (1990) used PCR to amplify the coding sequence of DHPR
from the messenger RNA of skin fibroblasts of a Lebanese child with
BH4-deficient hyperphenylalaninemia due to DHPR deficiency (HPABH4C;
261630), whose parents were consanguineous. Chemical cleavage of
mismatches indicated a mismatched thymine and cytosine at approximately
117 and 147 bases, respectively, from the end of the probe. Cloning and
sequencing of the mutant PCR products showed homozygous insertion of the
triplet ACT (threonine), after alanine 122 (base 390). Amplification of
a small region around this mutation by using genomic DNA as the PCR
target indicated that the mutation is completely within an exon. Unequal
crossing-over at the second base in the preceding alanine codon and
duplication of the bases CTA was suggested as the mechanism of
mutagenesis. The cleavage site 147 bases from the end of the probe
corresponded to the conversion of guanine to adenine at base 420 (CTG to
CTA) and did not alter the code for leucine. This was interpreted to be
a common neutral polymorphism because it was seen in another
DHPR-deficient child and in a control subject.
.0002
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, GLY23ASP
By screening the total coding sequence of a cDNA for DHPR by chemical
cleavage of mismatch and sequencing of selected portions, Dianzani et
al. (1993) identified a gly23-to-asp (G23D) mutation that seemed to be
particularly frequent in Mediterranean patients with
hyperphenylalaninemia due to dihydropteridine reductase deficiency
(261630). Its occurrence within a glycine string common to the
amino-terminal region in NADH-dependent enzymes suggested a possible
causal mechanism for the defect. See 612676.0006.
.0003
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TRP108GLY
In a patient with hyperphenylalaninemia due to dihydropteridine
reductase deficiency (261630), Dianzani et al. (1993) identified
homozygosity for a trp108-to-gly (W108G) substitution in the QDPR gene.
The mutation occurred in a motif that showed similarities with a region
of DHFR and conservation within different animal species.
.0004
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TRP36ARG
Ikeda et al. (1997) detected a homozygous trp36-to-arg (W36R) mutation
of the QDPR gene in a Japanese patient with hyperphenylalaninemia due to
DHPR deficiency (261630). The mutation abolished DHPR activity according
to an in vitro expression study. The patient was born to first-cousin
parents. Although hyperphenylalaninemia was detected in a newborn
screening program and she was placed on a low phenylalanine diet from
the age of 1 month with good control of serum phenylalanine level,
psychomotor development was delayed.
.0005
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, IVS3, A-G, 152-BP INS
In a Japanese boy with hyperphenylalaninemia due to DHPR deficiency
(261630), the offspring of first-cousin parents, Ikeda et al. (1997)
found a splicing error mutation. QDPR mRNA was markedly decreased.
RT-PCR of the mRNA generated a cDNA fragment with a 152-bp insertion.
The inserted sequence contained a termination codon, which probably
affected the stability of the mRNA. Analysis of genomic DNA showed that
the insertion was derived from the putative intron 3 of the QDPR gene,
and an intronic A-to-G substitution was present adjacent to the 3-prime
end of the inserted sequence. The nucleotide change generated a sequence
similar to an RNA splice donor site and probably activated an upstream
cryptic acceptor site, thus producing an abnormal extra exon. Creation
of intron-derived pseudoexons as a result of activation of an upstream
cryptic acceptor site seems to be a rare type of mutation. The patient
had 2 older brothers with hyperphenylalaninemia due to DHPR deficiency
Although a low phenylalanine diet was initiated, the patient showed
developmental delay and intractable seizures. His IQ was 30 at 11 years
of age.
.0006
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TYR150CYS
In a patient with hyperphenylalaninemia due to dihydropteridine
reductase deficiency (261630), Dianzani et al. (1998) identified a
tyr150-to-cys (Y150C) mutation in compound heterozygosity with G23D
(612676.0002), a mutation that is always associated with a severe
phenotype in homozygous patients. This patient had an intermediate
phenotype, with good response to monotherapy with BH4.
.0007
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TRP90TER
In 2 cousins and in a third unrelated patient with hyperphenylalaninemia
due to DHPR deficiency (261630), Romstad et al. (2000) identified a
350G-A transition in exon 3 of the QDPR gene causing a trp90-to-ter
(W90X) substitution. The peptide chain was predicted to be shortened by
155 amino acids. Although the phenotype was severe, all 3 patients
responded well to therapy.
*FIELD* SA
Kuhl et al. (1980)
*FIELD* RF
1. Brown, R. M.; Dahl, H.-H. M.: Localization of the human dihydropteridine
reductase gene to band p15.3 of chromosome 4 by in situ hybridization. Genomics 1:
67-70, 1987.
2. Dahl, H.-H. M.; Hutchinson, W.; McAdam, W.; Wake, S.; Morgan, F.
J.; Cotton, R. G. H.: Human dihydropteridine reductase: characterisation
of a cDNA clone and its use in analysis of patients with dihydropteridine
reductase deficiency. Nucleic Acids Res. 15: 1921-1932, 1987.
3. Dianzani, I.; de Sanctis, L.; Smooker, P. M.; Gough, T. J.; Alliaudi,
C.; Brusco, A.; Spada, M.; Blau, N.; Dobos, M.; Zhang, H.-P.; Yang,
N.; Ponzone, A.; Armarego, W. L. F.; Cotton, R. G. H.: Dihydropteridine
reductase deficiency: physical structure of the QDPR gene, identification
of two new mutations and genotype-phenotype correlations. Hum. Mutat. 12:
267-273, 1998.
4. Dianzani, I.; Howells, D. W.; Ponzone, A.; Saleeba, J. A.; Smooker,
P. M.; Cotton, R. G. H.: Two new mutations in the dihydropteridine
reductase gene in patients with tetrahydrobiopterin deficiency. J.
Med. Genet. 30: 465-469, 1993.
5. Howells, D. W.; Forrest, S. M.; Dahl, H.-H. M.; Cotton, R. G. H.
: Insertion of an extra codon for threonine is a cause of dihydropteridine
reductase deficiency. Am. J. Hum. Genet. 47: 279-285, 1990.
6. Ikeda, H.; Matsubara, Y.; Mikami, H.; Kure, S.; Owada, M.; Gough,
T.; Smooker, P. M.; Dobbs, M.; Dahl, H.-H. M.; Cotton, R. G. H.; Narisawa,
K.: Molecular analysis of dihydropteridine reductase deficiency:
identification of two novel mutations in Japanese patients. Hum.
Genet. 100: 637-642, 1997.
7. Kuhl, P.; Olek, K.; Wardenbach, P.: Dihydropteridine reductase
variation in man and the characid fish 'Cheirodon axelrodi': evidence
for a dimeric enzyme structure. Hum. Genet. 55: 99-102, 1980.
8. Kuhl, P.; Olek, K.; Wardenbach, P.; Grzeschik, K.-H.: Assignment
of a gene for human quinoid-dihydropteridine reductase (QDPR, EC 1.6.5.1)
to chromosome 4. Hum. Genet. 53: 47-49, 1979.
9. Lockyer, J.; Cook, R. G.; Milstien, S.; Kaufman, S.; Woo, S. L.
C.; Ledley, F. D.: Structure and expression of human dihydropteridine
reductase. Proc. Nat. Acad. Sci. 84: 3329-3333, 1987.
10. MacDonald, M. E.; Anderson, M. A.; Lockyer, J. L.; Milstien, S.;
Hobbs, W. J.; Faryniarz, A. G.; Kaufman, S.; Ledley, F. D.; Woo, S.
L. C.; Gusella, J. F.: Physical and genetic localization of quinonoid
dihydropteridine reductase gene (QDPR) on short arm of chromosome
4. Somat. Cell Molec. Genet. 13: 569-574, 1987.
11. Romstad, A.; Kalkanoglu, H. S.; Coskun, T.; Demirkol, M.; Tokatli,
A.; Dursun, A.; Baykal, T.; Ozalp, I.; Guldberg, P.; Guttler, F.:
Molecular analysis of 16 Turkish families with DHPR deficiency using
denaturing gradient gel electrophoresis (DGGE). Hum. Genet. 107:
546-553, 2000.
12. Smooker, P. M.; Cotton, R. G. H.: Molecular basis of dihydropteridine
reductase deficiency. Hum. Mutat. 5: 279-284, 1995.
13. Sumi, S.; Ishikawa, T.; Ito, Y.; Oishi, H.; Asai, K.; Wada, Y.
: Probable assignment of the dihydropteridine reductase gene to 4p15.31. Tohoku
J. Exp. Med. 160: 93-94, 1990.
*FIELD* CD
Carol A. Bocchini: 3/19/2009
*FIELD* ED
joanna: 03/05/2012
carol: 4/15/2009
ckniffin: 4/10/2009
carol: 3/19/2009
*RECORD*
*FIELD* NO
612676
*FIELD* TI
*612676 QUINOID DIHYDROPTERIDINE REDUCTASE; QDPR
;;DIHYDROPTERIDINE REDUCTASE; DHPR
read more*FIELD* TX
DESCRIPTION
Dihydropteridine reductase (EC 1.6.99.7) catalyzes the NADH-mediated
reduction of quinonoid dihydrobiopterin and is an essential component of
the pterin-dependent aromatic amino acid hydroxylating systems (Lockyer
et al., 1987).
CLONING
Dahl et al. (1987) and Lockyer et al. (1987) isolated a cDNA clone for
DHPR that spans the complete coding region and presented the nucleotide
sequence and predicted amino acid sequence of the protein. They found
that the 244-amino acid DHPR protein does not share extensive homology
with the enzymatically related protein dihydrofolate reductase (DHFR;
126060).
MAPPING
By study of mouse-human somatic cell hybrids, Kuhl et al. (1979) mapped
the structural gene for quinoid dihydropteridine reductase on chromosome
4.
MacDonald et al. (1987) used a portion of a cDNA clone corresponding to
the 3-prime end of the human QDPR mRNA as a probe to map that gene by
analysis of somatic cell hybrid lines. The regional localization
achieved was 4p16.1-p15.1. With the use of a RFLP demonstrated by the
probe, they showed only loose linkage of the gene to D4S10, the marker
of Huntington disease (143100). Thus, QDPR was excluded as a candidate
gene in HD.
Brown and Dahl (1987) reported the localization of the DHPR gene to
4p15.3 by in situ hybridization using a cDNA probe.
On the basis of 2 cases of dihydropteridine reductase deficiency
(261630) with overlapping deletions of 4p, Sumi et al. (1990) concluded
that the DHPR gene is probably located on 4p15.31.
MOLECULAR GENETICS
In a patient with BH4-deficient hyperphenylalaninemia due to
dihydropteridine reductase deficiency (HPABH4C; 261630), the offspring
of consanguineous parents, Howells et al. (1990) identified homozygosity
for a mutation in the QDPR gene (612676.0001).
Smooker and Cotton (1995) reviewed 12 point mutations that had been
described in DHPR cDNA, all of which resulted in dihydropteridine
reductase deficiency. The mutations resulted in amino acid
substitutions, insertions, or premature terminations. A further 2
mutations resulted in aberrant splicing of QDPR transcripts.
Romstad et al. (2000) studied 17 patients belonging to 16 Turkish
families with DHPR deficiency. The patients were detected at neonatal
screening for hyperphenylalaninemia or upon the development of
neurologic symptoms. A mutation screen of the entire open reading frame
and all splice sites of the QDPR gene identified 10 different mutations,
7 of which were novel (e.g., 612676.0007). Six of the mutations were
missense, 2 were nonsense, and 2 were frameshift mutations. All patients
had homoallelic genotypes, which allowed the establishment of
genotype-phenotype associations.
*FIELD* AV
.0001
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, 3-BP INS, 390ACT
Howells et al. (1990) used PCR to amplify the coding sequence of DHPR
from the messenger RNA of skin fibroblasts of a Lebanese child with
BH4-deficient hyperphenylalaninemia due to DHPR deficiency (HPABH4C;
261630), whose parents were consanguineous. Chemical cleavage of
mismatches indicated a mismatched thymine and cytosine at approximately
117 and 147 bases, respectively, from the end of the probe. Cloning and
sequencing of the mutant PCR products showed homozygous insertion of the
triplet ACT (threonine), after alanine 122 (base 390). Amplification of
a small region around this mutation by using genomic DNA as the PCR
target indicated that the mutation is completely within an exon. Unequal
crossing-over at the second base in the preceding alanine codon and
duplication of the bases CTA was suggested as the mechanism of
mutagenesis. The cleavage site 147 bases from the end of the probe
corresponded to the conversion of guanine to adenine at base 420 (CTG to
CTA) and did not alter the code for leucine. This was interpreted to be
a common neutral polymorphism because it was seen in another
DHPR-deficient child and in a control subject.
.0002
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, GLY23ASP
By screening the total coding sequence of a cDNA for DHPR by chemical
cleavage of mismatch and sequencing of selected portions, Dianzani et
al. (1993) identified a gly23-to-asp (G23D) mutation that seemed to be
particularly frequent in Mediterranean patients with
hyperphenylalaninemia due to dihydropteridine reductase deficiency
(261630). Its occurrence within a glycine string common to the
amino-terminal region in NADH-dependent enzymes suggested a possible
causal mechanism for the defect. See 612676.0006.
.0003
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TRP108GLY
In a patient with hyperphenylalaninemia due to dihydropteridine
reductase deficiency (261630), Dianzani et al. (1993) identified
homozygosity for a trp108-to-gly (W108G) substitution in the QDPR gene.
The mutation occurred in a motif that showed similarities with a region
of DHFR and conservation within different animal species.
.0004
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TRP36ARG
Ikeda et al. (1997) detected a homozygous trp36-to-arg (W36R) mutation
of the QDPR gene in a Japanese patient with hyperphenylalaninemia due to
DHPR deficiency (261630). The mutation abolished DHPR activity according
to an in vitro expression study. The patient was born to first-cousin
parents. Although hyperphenylalaninemia was detected in a newborn
screening program and she was placed on a low phenylalanine diet from
the age of 1 month with good control of serum phenylalanine level,
psychomotor development was delayed.
.0005
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, IVS3, A-G, 152-BP INS
In a Japanese boy with hyperphenylalaninemia due to DHPR deficiency
(261630), the offspring of first-cousin parents, Ikeda et al. (1997)
found a splicing error mutation. QDPR mRNA was markedly decreased.
RT-PCR of the mRNA generated a cDNA fragment with a 152-bp insertion.
The inserted sequence contained a termination codon, which probably
affected the stability of the mRNA. Analysis of genomic DNA showed that
the insertion was derived from the putative intron 3 of the QDPR gene,
and an intronic A-to-G substitution was present adjacent to the 3-prime
end of the inserted sequence. The nucleotide change generated a sequence
similar to an RNA splice donor site and probably activated an upstream
cryptic acceptor site, thus producing an abnormal extra exon. Creation
of intron-derived pseudoexons as a result of activation of an upstream
cryptic acceptor site seems to be a rare type of mutation. The patient
had 2 older brothers with hyperphenylalaninemia due to DHPR deficiency
Although a low phenylalanine diet was initiated, the patient showed
developmental delay and intractable seizures. His IQ was 30 at 11 years
of age.
.0006
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TYR150CYS
In a patient with hyperphenylalaninemia due to dihydropteridine
reductase deficiency (261630), Dianzani et al. (1998) identified a
tyr150-to-cys (Y150C) mutation in compound heterozygosity with G23D
(612676.0002), a mutation that is always associated with a severe
phenotype in homozygous patients. This patient had an intermediate
phenotype, with good response to monotherapy with BH4.
.0007
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C
QDPR, TRP90TER
In 2 cousins and in a third unrelated patient with hyperphenylalaninemia
due to DHPR deficiency (261630), Romstad et al. (2000) identified a
350G-A transition in exon 3 of the QDPR gene causing a trp90-to-ter
(W90X) substitution. The peptide chain was predicted to be shortened by
155 amino acids. Although the phenotype was severe, all 3 patients
responded well to therapy.
*FIELD* SA
Kuhl et al. (1980)
*FIELD* RF
1. Brown, R. M.; Dahl, H.-H. M.: Localization of the human dihydropteridine
reductase gene to band p15.3 of chromosome 4 by in situ hybridization. Genomics 1:
67-70, 1987.
2. Dahl, H.-H. M.; Hutchinson, W.; McAdam, W.; Wake, S.; Morgan, F.
J.; Cotton, R. G. H.: Human dihydropteridine reductase: characterisation
of a cDNA clone and its use in analysis of patients with dihydropteridine
reductase deficiency. Nucleic Acids Res. 15: 1921-1932, 1987.
3. Dianzani, I.; de Sanctis, L.; Smooker, P. M.; Gough, T. J.; Alliaudi,
C.; Brusco, A.; Spada, M.; Blau, N.; Dobos, M.; Zhang, H.-P.; Yang,
N.; Ponzone, A.; Armarego, W. L. F.; Cotton, R. G. H.: Dihydropteridine
reductase deficiency: physical structure of the QDPR gene, identification
of two new mutations and genotype-phenotype correlations. Hum. Mutat. 12:
267-273, 1998.
4. Dianzani, I.; Howells, D. W.; Ponzone, A.; Saleeba, J. A.; Smooker,
P. M.; Cotton, R. G. H.: Two new mutations in the dihydropteridine
reductase gene in patients with tetrahydrobiopterin deficiency. J.
Med. Genet. 30: 465-469, 1993.
5. Howells, D. W.; Forrest, S. M.; Dahl, H.-H. M.; Cotton, R. G. H.
: Insertion of an extra codon for threonine is a cause of dihydropteridine
reductase deficiency. Am. J. Hum. Genet. 47: 279-285, 1990.
6. Ikeda, H.; Matsubara, Y.; Mikami, H.; Kure, S.; Owada, M.; Gough,
T.; Smooker, P. M.; Dobbs, M.; Dahl, H.-H. M.; Cotton, R. G. H.; Narisawa,
K.: Molecular analysis of dihydropteridine reductase deficiency:
identification of two novel mutations in Japanese patients. Hum.
Genet. 100: 637-642, 1997.
7. Kuhl, P.; Olek, K.; Wardenbach, P.: Dihydropteridine reductase
variation in man and the characid fish 'Cheirodon axelrodi': evidence
for a dimeric enzyme structure. Hum. Genet. 55: 99-102, 1980.
8. Kuhl, P.; Olek, K.; Wardenbach, P.; Grzeschik, K.-H.: Assignment
of a gene for human quinoid-dihydropteridine reductase (QDPR, EC 1.6.5.1)
to chromosome 4. Hum. Genet. 53: 47-49, 1979.
9. Lockyer, J.; Cook, R. G.; Milstien, S.; Kaufman, S.; Woo, S. L.
C.; Ledley, F. D.: Structure and expression of human dihydropteridine
reductase. Proc. Nat. Acad. Sci. 84: 3329-3333, 1987.
10. MacDonald, M. E.; Anderson, M. A.; Lockyer, J. L.; Milstien, S.;
Hobbs, W. J.; Faryniarz, A. G.; Kaufman, S.; Ledley, F. D.; Woo, S.
L. C.; Gusella, J. F.: Physical and genetic localization of quinonoid
dihydropteridine reductase gene (QDPR) on short arm of chromosome
4. Somat. Cell Molec. Genet. 13: 569-574, 1987.
11. Romstad, A.; Kalkanoglu, H. S.; Coskun, T.; Demirkol, M.; Tokatli,
A.; Dursun, A.; Baykal, T.; Ozalp, I.; Guldberg, P.; Guttler, F.:
Molecular analysis of 16 Turkish families with DHPR deficiency using
denaturing gradient gel electrophoresis (DGGE). Hum. Genet. 107:
546-553, 2000.
12. Smooker, P. M.; Cotton, R. G. H.: Molecular basis of dihydropteridine
reductase deficiency. Hum. Mutat. 5: 279-284, 1995.
13. Sumi, S.; Ishikawa, T.; Ito, Y.; Oishi, H.; Asai, K.; Wada, Y.
: Probable assignment of the dihydropteridine reductase gene to 4p15.31. Tohoku
J. Exp. Med. 160: 93-94, 1990.
*FIELD* CD
Carol A. Bocchini: 3/19/2009
*FIELD* ED
joanna: 03/05/2012
carol: 4/15/2009
ckniffin: 4/10/2009
carol: 3/19/2009