Full text data of PRPS1
PRPS1
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ribose-phosphate pyrophosphokinase 1; 2.7.6.1 (PPRibP; Phosphoribosyl pyrophosphate synthase I; PRS-I)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ribose-phosphate pyrophosphokinase 1; 2.7.6.1 (PPRibP; Phosphoribosyl pyrophosphate synthase I; PRS-I)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00219616
IPI00219616 PhosPhoribosyl PyroPhosPhate synthetase 1 Lymph, utilized by both the de novo and the salvage pathways by which endogenously formed or exogenously added pyrimidine, purine, or pyridine bases are converted to the corresponding ribonucleoside monophosphates 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
IPI00219616 PhosPhoribosyl PyroPhosPhate synthetase 1 Lymph, utilized by both the de novo and the salvage pathways by which endogenously formed or exogenously added pyrimidine, purine, or pyridine bases are converted to the corresponding ribonucleoside monophosphates 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
P60891
ID PRPS1_HUMAN Reviewed; 318 AA.
AC P60891; B1ALA8; D3DUX6; P09329;
DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Ribose-phosphate pyrophosphokinase 1;
DE EC=2.7.6.1;
DE AltName: Full=PPRibP;
DE AltName: Full=Phosphoribosyl pyrophosphate synthase I;
DE Short=PRS-I;
GN Name=PRPS1;
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].
RC TISSUE=Lymphoblast;
RX PubMed=2155397; DOI=10.1093/nar/18.1.193;
RA Roessler B.J., Bell G., Heidler S., Seino S., Becker M., Palella T.D.;
RT "Cloning of two distinct copies of human phosphoribosylpyrophosphate
RT synthetase cDNA.";
RL Nucleic Acids Res. 18:193-193(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1650777;
RA Sonoda T., Taira M., Ishijima S., Ishizuka T., Iizaka T., Tatibana M.;
RT "Complete nucleotide sequence of human phosphoribosyl pyrophosphate
RT synthetase subunit I (PRS I) cDNA and a comparison with human and rat
RT PRPS gene families.";
RL J. Biochem. 109:361-364(1991).
RN [3]
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 [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-41.
RX PubMed=1314091; DOI=10.1016/0167-4781(92)90521-Z;
RA Ishizuka T., Iizasa T., Taira M., Ishijima S., Sonoda T., Shimada H.,
RA Nagatake N., Tatibana M.;
RT "Promoter regions of the human X-linked housekeeping genes PRPS1 and
RT PRPS2 encoding phosphoribosylpyrophosphate synthetase subunit I and II
RT isoforms.";
RL Biochim. Biophys. Acta 1130:139-148(1992).
RN [7]
RP PROTEIN SEQUENCE OF 2-33; 85-96; 164-176; 205-214; 236-260 AND
RP 303-318, CLEAVAGE OF INITIATOR METHIONINE, LACK OF N-TERMINAL
RP ACETYLATION, AND MASS SPECTROMETRY.
RC TISSUE=Colon carcinoma;
RA Bienvenut W.V., Zebisch A., Kolch W.;
RL Submitted (JUL-2009) to UniProtKB.
RN [8]
RP PROTEIN SEQUENCE OF 244-260 AND 303-318, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [9]
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 [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH AMP, SUBUNIT,
RP AND MUTAGENESIS OF SER-132; ASN-144 AND TYR-146.
RX PubMed=16939420; DOI=10.1042/BJ20061066;
RA Li S., Lu Y., Peng B., Ding J.;
RT "Crystal structure of human phosphoribosylpyrophosphate synthetase 1
RT reveals a novel allosteric site.";
RL Biochem. J. 401:39-47(2007).
RN [11]
RP VARIANTS PRPS1 SUPERACTIVITY SER-114 AND HIS-183.
RA Roessler B.J., Palella T.D., Heidler S., Becker M.A.;
RT "Identification of distinct PRPS1 mutations in two patients with X-
RT linked phosphoribosylpyrophosphate synthetase superactivity.";
RL Clin. Res. 39:267A-267A(1991).
RN [12]
RP VARIANTS PRPS1 SUPERACTIVITY HIS-52; SER-114; ILE-129; HIS-183;
RP VAL-190 AND GLN-193.
RX PubMed=7593598; DOI=10.1172/JCI118267;
RA Becker M.A., Smith P.R., Taylor W., Mustafi R., Switzer R.L.;
RT "The genetic and functional basis of purine nucleotide feedback-
RT resistant phosphoribosylpyrophosphate synthetase superactivity.";
RL J. Clin. Invest. 96:2133-2141(1995).
RN [13]
RP VARIANTS [LARGE SCALE ANALYSIS] HIS-203; GLY-219 AND ASP-231.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [14]
RP VARIANTS ARTS PRO-133 AND PRO-152.
RX PubMed=17701896; DOI=10.1086/520706;
RA de Brouwer A.P.M., Williams K.L., Duley J.A., van Kuilenburg A.B.P.,
RA Nabuurs S.B., Egmont-Petersen M., Lugtenberg D., Zoetekouw L.,
RA Banning M.J.G., Roeffen M., Hamel B.C.J., Weaving L., Ouvrier R.A.,
RA Donald J.A., Wevers R.A., Christodoulou J., van Bokhoven H.;
RT "Arts syndrome is caused by loss-of-function mutations in PRPS1.";
RL Am. J. Hum. Genet. 81:507-518(2007).
RN [15]
RP VARIANTS CMTX5 ASP-43 AND THR-115.
RX PubMed=17701900; DOI=10.1086/519529;
RA Kim H.-J., Sohn K.-M., Shy M.E., Krajewski K.M., Hwang M., Park J.-H.,
RA Jang S.-Y., Won H.-H., Choi B.-O., Hong S.H., Kim B.-J., Suh Y.-L.,
RA Ki C.-S., Lee S.-Y., Kim S.-H., Kim J.-W.;
RT "Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate
RT synthetase enzyme critical for nucleotide biosynthesis, cause
RT hereditary peripheral neuropathy with hearing loss and optic
RT neuropathy (cmtx5).";
RL Am. J. Hum. Genet. 81:552-558(2007).
RN [16]
RP VARIANTS DFNX1 ASN-65; THR-87; THR-290 AND ARG-306.
RX PubMed=20021999; DOI=10.1016/j.ajhg.2009.11.015;
RA Liu X., Han D., Li J., Han B., Ouyang X., Cheng J., Li X., Jin Z.,
RA Wang Y., Bitner-Glindzicz M., Kong X., Xu H., Kantardzhieva A.,
RA Eavey R.D., Seidman C.E., Seidman J.G., Du L.L., Chen Z.Y., Dai P.,
RA Teng M., Yan D., Yuan H.;
RT "Loss-of-function mutations in the PRPS1 gene cause a type of
RT nonsyndromic X-linked sensorineural deafness, DFN2.";
RL Am. J. Hum. Genet. 86:65-71(2010).
CC -!- FUNCTION: Catalyzes the synthesis of phosphoribosylpyrophosphate
CC (PRPP) that is essential for nucleotide synthesis.
CC -!- CATALYTIC ACTIVITY: ATP + D-ribose 5-phosphate = AMP + 5-phospho-
CC alpha-D-ribose 1-diphosphate.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Activated by magnesium and inorganic phosphate.
CC -!- PATHWAY: Metabolic intermediate biosynthesis; 5-phospho-alpha-D-
CC ribose 1-diphosphate biosynthesis; 5-phospho-alpha-D-ribose 1-
CC diphosphate from D-ribose 5-phosphate (route I): step 1/1.
CC -!- SUBUNIT: Homodimer. The active form is probably a hexamer composed
CC of 3 homodimers.
CC -!- DISEASE: Phosphoribosylpyrophosphate synthetase superactivity
CC (PRPS1 superactivity) [MIM:300661]: Familial disorder
CC characterized by excessive purine production, gout and uric acid
CC urolithiasis. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Charcot-Marie-Tooth disease, X-linked recessive, 5
CC (CMTX5) [MIM:311070]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by
CC progressive weakness and atrophy, initially of the peroneal
CC muscles and later of the distal muscles of the arms. Charcot-
CC Marie-Tooth disease is classified in two main groups on the basis
CC of electrophysiologic properties and histopathology: primary
CC peripheral demyelinating neuropathies characterized by severely
CC reduced motor nerve conduction velocities (NCVs) (less than 38m/s)
CC and segmental demyelination and remyelination, and primary
CC peripheral axonal neuropathies characterized by normal or mildly
CC reduced NCVs and chronic axonal degeneration and regeneration on
CC nerve biopsy. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: ARTS syndrome (ARTS) [MIM:301835]: A disorder
CC characterized by mental retardation, early-onset hypotonia,
CC ataxia, delayed motor development, hearing impairment, and optic
CC atrophy. Susceptibility to infections, especially of the upper
CC respiratory tract, can result in early death. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Deafness, X-linked, 1 (DFNX1) [MIM:304500]: A form of
CC deafness characterized by progressive, severe-to-profound
CC sensorineural hearing loss in males. Females manifest mild to
CC moderate hearing loss. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ribose-phosphate pyrophosphokinase
CC family.
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DR EMBL; X15331; CAA33386.1; -; mRNA.
DR EMBL; D00860; BAA00733.1; -; mRNA.
DR EMBL; AL137787; CAI42173.1; -; Genomic_DNA.
DR EMBL; AL772400; CAI42173.1; JOINED; Genomic_DNA.
DR EMBL; AL772400; CAI41098.1; -; Genomic_DNA.
DR EMBL; AL137787; CAI41098.1; JOINED; Genomic_DNA.
DR EMBL; CH471120; EAX02709.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02710.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02711.1; -; Genomic_DNA.
DR EMBL; BC001605; AAH01605.1; -; mRNA.
DR PIR; JX0159; KIHUR1.
DR RefSeq; NP_001191331.1; NM_001204402.1.
DR RefSeq; NP_002755.1; NM_002764.3.
DR UniGene; Hs.56; -.
DR PDB; 2H06; X-ray; 2.20 A; A/B=1-318.
DR PDB; 2H07; X-ray; 2.20 A; A/B=1-318.
DR PDB; 2H08; X-ray; 2.50 A; A/B=1-318.
DR PDB; 2HCR; X-ray; 2.20 A; A/B=1-318.
DR PDB; 3EFH; X-ray; 2.60 A; A/B=1-318.
DR PDB; 3S5J; X-ray; 2.02 A; A/B=1-318.
DR PDB; 4F8E; X-ray; 2.27 A; A/B=1-318.
DR PDBsum; 2H06; -.
DR PDBsum; 2H07; -.
DR PDBsum; 2H08; -.
DR PDBsum; 2HCR; -.
DR PDBsum; 3EFH; -.
DR PDBsum; 3S5J; -.
DR PDBsum; 4F8E; -.
DR ProteinModelPortal; P60891; -.
DR SMR; P60891; 3-317.
DR IntAct; P60891; 3.
DR STRING; 9606.ENSP00000361512; -.
DR BindingDB; P60891; -.
DR ChEMBL; CHEMBL2638; -.
DR PhosphoSite; P60891; -.
DR DMDM; 46397477; -.
DR UCD-2DPAGE; P60891; -.
DR PaxDb; P60891; -.
DR PRIDE; P60891; -.
DR DNASU; 5631; -.
DR Ensembl; ENST00000372435; ENSP00000361512; ENSG00000147224.
DR Ensembl; ENST00000543248; ENSP00000443185; ENSG00000147224.
DR GeneID; 5631; -.
DR KEGG; hsa:5631; -.
DR UCSC; uc004ene.4; human.
DR CTD; 5631; -.
DR GeneCards; GC0XP106871; -.
DR HGNC; HGNC:9462; PRPS1.
DR MIM; 300661; phenotype.
DR MIM; 301835; phenotype.
DR MIM; 304500; phenotype.
DR MIM; 311070; phenotype.
DR MIM; 311850; gene.
DR neXtProt; NX_P60891; -.
DR Orphanet; 1187; Lethal ataxia with deafness and optic atrophy.
DR Orphanet; 3222; Phosphoribosylpyrophosphate synthetase superactivity.
DR Orphanet; 99014; X-linked Charcot-Marie-Tooth disease type 5.
DR Orphanet; 90625; X-linked nonsyndromic sensorineural deafness type DFN.
DR PharmGKB; PA33817; -.
DR eggNOG; COG0462; -.
DR HOGENOM; HOG000210451; -.
DR HOVERGEN; HBG001520; -.
DR InParanoid; P60891; -.
DR KO; K00948; -.
DR OMA; MMFAEAV; -.
DR OrthoDB; EOG7G4QG5; -.
DR PhylomeDB; P60891; -.
DR BioCyc; MetaCyc:HS07410-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00087; UER00172.
DR ChiTaRS; PRPS1; human.
DR EvolutionaryTrace; P60891; -.
DR GenomeRNAi; 5631; -.
DR NextBio; 21886; -.
DR PRO; PR:P60891; -.
DR ArrayExpress; P60891; -.
DR Bgee; P60891; -.
DR CleanEx; HS_PRPS1; -.
DR Genevestigator; P60891; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0016301; F:kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004749; F:ribose phosphate diphosphokinase activity; IDA:UniProtKB.
DR GO; GO:0006015; P:5-phosphoribose 1-diphosphate biosynthetic process; TAS:Reactome.
DR GO; GO:0005975; P:carbohydrate metabolic process; TAS:Reactome.
DR GO; GO:0046101; P:hypoxanthine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0007399; P:nervous system development; IMP:UniProtKB.
DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006221; P:pyrimidine nucleotide biosynthetic process; NAS:UniProtKB.
DR GO; GO:0009156; P:ribonucleoside monophosphate biosynthetic process; IEA:InterPro.
DR GO; GO:0034418; P:urate biosynthetic process; IMP:UniProtKB.
DR InterPro; IPR000842; PRib_PP_synth_CS.
DR InterPro; IPR005946; Rib-P_diPkinase.
DR Pfam; PF14572; Pribosyl_synth; 1.
DR TIGRFAMs; TIGR01251; ribP_PPkin; 1.
DR PROSITE; PS00114; PRPP_SYNTHASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Charcot-Marie-Tooth disease;
KW Complete proteome; Deafness; Direct protein sequencing;
KW Disease mutation; Gout; Kinase; Magnesium; Mental retardation;
KW Metal-binding; Neuropathy; Non-syndromic deafness;
KW Nucleotide biosynthesis; Nucleotide-binding; Polymorphism;
KW Reference proteome; Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 318 Ribose-phosphate pyrophosphokinase 1.
FT /FTId=PRO_0000141071.
FT NP_BIND 96 101 ATP.
FT REGION 212 227 Binding of phosphoribosylpyrophosphate
FT (Potential).
FT METAL 128 128 Magnesium (Potential).
FT METAL 130 130 Magnesium (Potential).
FT METAL 139 139 Magnesium (Potential).
FT METAL 143 143 Magnesium (Potential).
FT BINDING 130 130 ATP.
FT VARIANT 43 43 E -> D (in CMTX5).
FT /FTId=VAR_036941.
FT VARIANT 52 52 D -> H (in PRPS1 superactivity).
FT /FTId=VAR_016044.
FT VARIANT 65 65 D -> N (in DFNX1).
FT /FTId=VAR_063522.
FT VARIANT 87 87 A -> T (in DFNX1).
FT /FTId=VAR_063523.
FT VARIANT 114 114 N -> S (in PRPS1 superactivity).
FT /FTId=VAR_004163.
FT VARIANT 115 115 M -> T (in CMTX5).
FT /FTId=VAR_036942.
FT VARIANT 129 129 L -> I (in PRPS1 superactivity).
FT /FTId=VAR_016045.
FT VARIANT 133 133 Q -> P (in ARTS).
FT /FTId=VAR_036943.
FT VARIANT 152 152 L -> P (in ARTS).
FT /FTId=VAR_036944.
FT VARIANT 183 183 D -> H (in PRPS1 superactivity).
FT /FTId=VAR_004164.
FT VARIANT 190 190 A -> V (in PRPS1 superactivity).
FT /FTId=VAR_016046.
FT VARIANT 193 193 H -> Q (in PRPS1 superactivity).
FT /FTId=VAR_016047.
FT VARIANT 203 203 D -> H (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036593.
FT VARIANT 219 219 V -> G (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036594.
FT VARIANT 231 231 H -> D (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036595.
FT VARIANT 290 290 I -> T (in DFNX1).
FT /FTId=VAR_063524.
FT VARIANT 306 306 G -> R (in DFNX1).
FT /FTId=VAR_063525.
FT MUTAGEN 132 132 S->A: Reduces catalytic activity.
FT MUTAGEN 132 132 S->F: No effect on catalytic activity.
FT MUTAGEN 144 144 N->H: No effect on catalytic activity.
FT MUTAGEN 146 146 Y->F: No effect on catalytic activity.
FT MUTAGEN 146 146 Y->M: Reduces catalytic activity.
FT STRAND 4 8
FT HELIX 14 22
FT STRAND 30 34
FT STRAND 36 38
FT STRAND 40 44
FT STRAND 52 56
FT HELIX 63 79
FT STRAND 83 91
FT TURN 93 96
FT STRAND 101 104
FT HELIX 108 119
FT STRAND 122 128
FT HELIX 132 137
FT STRAND 142 145
FT HELIX 148 158
FT HELIX 162 164
FT STRAND 166 171
FT HELIX 172 174
FT HELIX 175 185
FT STRAND 188 194
FT STRAND 205 209
FT STRAND 214 225
FT HELIX 227 238
FT STRAND 242 251
FT HELIX 257 263
FT STRAND 267 272
FT HELIX 278 282
FT STRAND 287 290
FT HELIX 293 305
FT HELIX 310 313
SQ SEQUENCE 318 AA; 34834 MW; 46D017E969908BA0 CRC64;
MPNIKIFSGS SHQDLSQKIA DRLGLELGKV VTKKFSNQET CVEIGESVRG EDVYIVQSGC
GEINDNLMEL LIMINACKIA SASRVTAVIP CFPYARQDKK DKSRAPISAK LVANMLSVAG
ADHIITMDLH ASQIQGFFDI PVDNLYAEPA VLKWIRENIS EWRNCTIVSP DAGGAKRVTS
IADRLNVDFA LIHKERKKAN EVDRMVLVGD VKDRVAILVD DMADTCGTIC HAADKLLSAG
ATRVYAILTH GIFSGPAISR INNACFEAVV VTNTIPQEDK MKHCSKIQVI DISMILAEAI
RRTHNGESVS YLFSHVPL
//
ID PRPS1_HUMAN Reviewed; 318 AA.
AC P60891; B1ALA8; D3DUX6; P09329;
DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Ribose-phosphate pyrophosphokinase 1;
DE EC=2.7.6.1;
DE AltName: Full=PPRibP;
DE AltName: Full=Phosphoribosyl pyrophosphate synthase I;
DE Short=PRS-I;
GN Name=PRPS1;
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].
RC TISSUE=Lymphoblast;
RX PubMed=2155397; DOI=10.1093/nar/18.1.193;
RA Roessler B.J., Bell G., Heidler S., Seino S., Becker M., Palella T.D.;
RT "Cloning of two distinct copies of human phosphoribosylpyrophosphate
RT synthetase cDNA.";
RL Nucleic Acids Res. 18:193-193(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1650777;
RA Sonoda T., Taira M., Ishijima S., Ishizuka T., Iizaka T., Tatibana M.;
RT "Complete nucleotide sequence of human phosphoribosyl pyrophosphate
RT synthetase subunit I (PRS I) cDNA and a comparison with human and rat
RT PRPS gene families.";
RL J. Biochem. 109:361-364(1991).
RN [3]
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 [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-41.
RX PubMed=1314091; DOI=10.1016/0167-4781(92)90521-Z;
RA Ishizuka T., Iizasa T., Taira M., Ishijima S., Sonoda T., Shimada H.,
RA Nagatake N., Tatibana M.;
RT "Promoter regions of the human X-linked housekeeping genes PRPS1 and
RT PRPS2 encoding phosphoribosylpyrophosphate synthetase subunit I and II
RT isoforms.";
RL Biochim. Biophys. Acta 1130:139-148(1992).
RN [7]
RP PROTEIN SEQUENCE OF 2-33; 85-96; 164-176; 205-214; 236-260 AND
RP 303-318, CLEAVAGE OF INITIATOR METHIONINE, LACK OF N-TERMINAL
RP ACETYLATION, AND MASS SPECTROMETRY.
RC TISSUE=Colon carcinoma;
RA Bienvenut W.V., Zebisch A., Kolch W.;
RL Submitted (JUL-2009) to UniProtKB.
RN [8]
RP PROTEIN SEQUENCE OF 244-260 AND 303-318, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [9]
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 [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH AMP, SUBUNIT,
RP AND MUTAGENESIS OF SER-132; ASN-144 AND TYR-146.
RX PubMed=16939420; DOI=10.1042/BJ20061066;
RA Li S., Lu Y., Peng B., Ding J.;
RT "Crystal structure of human phosphoribosylpyrophosphate synthetase 1
RT reveals a novel allosteric site.";
RL Biochem. J. 401:39-47(2007).
RN [11]
RP VARIANTS PRPS1 SUPERACTIVITY SER-114 AND HIS-183.
RA Roessler B.J., Palella T.D., Heidler S., Becker M.A.;
RT "Identification of distinct PRPS1 mutations in two patients with X-
RT linked phosphoribosylpyrophosphate synthetase superactivity.";
RL Clin. Res. 39:267A-267A(1991).
RN [12]
RP VARIANTS PRPS1 SUPERACTIVITY HIS-52; SER-114; ILE-129; HIS-183;
RP VAL-190 AND GLN-193.
RX PubMed=7593598; DOI=10.1172/JCI118267;
RA Becker M.A., Smith P.R., Taylor W., Mustafi R., Switzer R.L.;
RT "The genetic and functional basis of purine nucleotide feedback-
RT resistant phosphoribosylpyrophosphate synthetase superactivity.";
RL J. Clin. Invest. 96:2133-2141(1995).
RN [13]
RP VARIANTS [LARGE SCALE ANALYSIS] HIS-203; GLY-219 AND ASP-231.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [14]
RP VARIANTS ARTS PRO-133 AND PRO-152.
RX PubMed=17701896; DOI=10.1086/520706;
RA de Brouwer A.P.M., Williams K.L., Duley J.A., van Kuilenburg A.B.P.,
RA Nabuurs S.B., Egmont-Petersen M., Lugtenberg D., Zoetekouw L.,
RA Banning M.J.G., Roeffen M., Hamel B.C.J., Weaving L., Ouvrier R.A.,
RA Donald J.A., Wevers R.A., Christodoulou J., van Bokhoven H.;
RT "Arts syndrome is caused by loss-of-function mutations in PRPS1.";
RL Am. J. Hum. Genet. 81:507-518(2007).
RN [15]
RP VARIANTS CMTX5 ASP-43 AND THR-115.
RX PubMed=17701900; DOI=10.1086/519529;
RA Kim H.-J., Sohn K.-M., Shy M.E., Krajewski K.M., Hwang M., Park J.-H.,
RA Jang S.-Y., Won H.-H., Choi B.-O., Hong S.H., Kim B.-J., Suh Y.-L.,
RA Ki C.-S., Lee S.-Y., Kim S.-H., Kim J.-W.;
RT "Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate
RT synthetase enzyme critical for nucleotide biosynthesis, cause
RT hereditary peripheral neuropathy with hearing loss and optic
RT neuropathy (cmtx5).";
RL Am. J. Hum. Genet. 81:552-558(2007).
RN [16]
RP VARIANTS DFNX1 ASN-65; THR-87; THR-290 AND ARG-306.
RX PubMed=20021999; DOI=10.1016/j.ajhg.2009.11.015;
RA Liu X., Han D., Li J., Han B., Ouyang X., Cheng J., Li X., Jin Z.,
RA Wang Y., Bitner-Glindzicz M., Kong X., Xu H., Kantardzhieva A.,
RA Eavey R.D., Seidman C.E., Seidman J.G., Du L.L., Chen Z.Y., Dai P.,
RA Teng M., Yan D., Yuan H.;
RT "Loss-of-function mutations in the PRPS1 gene cause a type of
RT nonsyndromic X-linked sensorineural deafness, DFN2.";
RL Am. J. Hum. Genet. 86:65-71(2010).
CC -!- FUNCTION: Catalyzes the synthesis of phosphoribosylpyrophosphate
CC (PRPP) that is essential for nucleotide synthesis.
CC -!- CATALYTIC ACTIVITY: ATP + D-ribose 5-phosphate = AMP + 5-phospho-
CC alpha-D-ribose 1-diphosphate.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Activated by magnesium and inorganic phosphate.
CC -!- PATHWAY: Metabolic intermediate biosynthesis; 5-phospho-alpha-D-
CC ribose 1-diphosphate biosynthesis; 5-phospho-alpha-D-ribose 1-
CC diphosphate from D-ribose 5-phosphate (route I): step 1/1.
CC -!- SUBUNIT: Homodimer. The active form is probably a hexamer composed
CC of 3 homodimers.
CC -!- DISEASE: Phosphoribosylpyrophosphate synthetase superactivity
CC (PRPS1 superactivity) [MIM:300661]: Familial disorder
CC characterized by excessive purine production, gout and uric acid
CC urolithiasis. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Charcot-Marie-Tooth disease, X-linked recessive, 5
CC (CMTX5) [MIM:311070]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by
CC progressive weakness and atrophy, initially of the peroneal
CC muscles and later of the distal muscles of the arms. Charcot-
CC Marie-Tooth disease is classified in two main groups on the basis
CC of electrophysiologic properties and histopathology: primary
CC peripheral demyelinating neuropathies characterized by severely
CC reduced motor nerve conduction velocities (NCVs) (less than 38m/s)
CC and segmental demyelination and remyelination, and primary
CC peripheral axonal neuropathies characterized by normal or mildly
CC reduced NCVs and chronic axonal degeneration and regeneration on
CC nerve biopsy. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: ARTS syndrome (ARTS) [MIM:301835]: A disorder
CC characterized by mental retardation, early-onset hypotonia,
CC ataxia, delayed motor development, hearing impairment, and optic
CC atrophy. Susceptibility to infections, especially of the upper
CC respiratory tract, can result in early death. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Deafness, X-linked, 1 (DFNX1) [MIM:304500]: A form of
CC deafness characterized by progressive, severe-to-profound
CC sensorineural hearing loss in males. Females manifest mild to
CC moderate hearing loss. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ribose-phosphate pyrophosphokinase
CC family.
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DR EMBL; X15331; CAA33386.1; -; mRNA.
DR EMBL; D00860; BAA00733.1; -; mRNA.
DR EMBL; AL137787; CAI42173.1; -; Genomic_DNA.
DR EMBL; AL772400; CAI42173.1; JOINED; Genomic_DNA.
DR EMBL; AL772400; CAI41098.1; -; Genomic_DNA.
DR EMBL; AL137787; CAI41098.1; JOINED; Genomic_DNA.
DR EMBL; CH471120; EAX02709.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02710.1; -; Genomic_DNA.
DR EMBL; CH471120; EAX02711.1; -; Genomic_DNA.
DR EMBL; BC001605; AAH01605.1; -; mRNA.
DR PIR; JX0159; KIHUR1.
DR RefSeq; NP_001191331.1; NM_001204402.1.
DR RefSeq; NP_002755.1; NM_002764.3.
DR UniGene; Hs.56; -.
DR PDB; 2H06; X-ray; 2.20 A; A/B=1-318.
DR PDB; 2H07; X-ray; 2.20 A; A/B=1-318.
DR PDB; 2H08; X-ray; 2.50 A; A/B=1-318.
DR PDB; 2HCR; X-ray; 2.20 A; A/B=1-318.
DR PDB; 3EFH; X-ray; 2.60 A; A/B=1-318.
DR PDB; 3S5J; X-ray; 2.02 A; A/B=1-318.
DR PDB; 4F8E; X-ray; 2.27 A; A/B=1-318.
DR PDBsum; 2H06; -.
DR PDBsum; 2H07; -.
DR PDBsum; 2H08; -.
DR PDBsum; 2HCR; -.
DR PDBsum; 3EFH; -.
DR PDBsum; 3S5J; -.
DR PDBsum; 4F8E; -.
DR ProteinModelPortal; P60891; -.
DR SMR; P60891; 3-317.
DR IntAct; P60891; 3.
DR STRING; 9606.ENSP00000361512; -.
DR BindingDB; P60891; -.
DR ChEMBL; CHEMBL2638; -.
DR PhosphoSite; P60891; -.
DR DMDM; 46397477; -.
DR UCD-2DPAGE; P60891; -.
DR PaxDb; P60891; -.
DR PRIDE; P60891; -.
DR DNASU; 5631; -.
DR Ensembl; ENST00000372435; ENSP00000361512; ENSG00000147224.
DR Ensembl; ENST00000543248; ENSP00000443185; ENSG00000147224.
DR GeneID; 5631; -.
DR KEGG; hsa:5631; -.
DR UCSC; uc004ene.4; human.
DR CTD; 5631; -.
DR GeneCards; GC0XP106871; -.
DR HGNC; HGNC:9462; PRPS1.
DR MIM; 300661; phenotype.
DR MIM; 301835; phenotype.
DR MIM; 304500; phenotype.
DR MIM; 311070; phenotype.
DR MIM; 311850; gene.
DR neXtProt; NX_P60891; -.
DR Orphanet; 1187; Lethal ataxia with deafness and optic atrophy.
DR Orphanet; 3222; Phosphoribosylpyrophosphate synthetase superactivity.
DR Orphanet; 99014; X-linked Charcot-Marie-Tooth disease type 5.
DR Orphanet; 90625; X-linked nonsyndromic sensorineural deafness type DFN.
DR PharmGKB; PA33817; -.
DR eggNOG; COG0462; -.
DR HOGENOM; HOG000210451; -.
DR HOVERGEN; HBG001520; -.
DR InParanoid; P60891; -.
DR KO; K00948; -.
DR OMA; MMFAEAV; -.
DR OrthoDB; EOG7G4QG5; -.
DR PhylomeDB; P60891; -.
DR BioCyc; MetaCyc:HS07410-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00087; UER00172.
DR ChiTaRS; PRPS1; human.
DR EvolutionaryTrace; P60891; -.
DR GenomeRNAi; 5631; -.
DR NextBio; 21886; -.
DR PRO; PR:P60891; -.
DR ArrayExpress; P60891; -.
DR Bgee; P60891; -.
DR CleanEx; HS_PRPS1; -.
DR Genevestigator; P60891; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0016301; F:kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004749; F:ribose phosphate diphosphokinase activity; IDA:UniProtKB.
DR GO; GO:0006015; P:5-phosphoribose 1-diphosphate biosynthetic process; TAS:Reactome.
DR GO; GO:0005975; P:carbohydrate metabolic process; TAS:Reactome.
DR GO; GO:0046101; P:hypoxanthine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0007399; P:nervous system development; IMP:UniProtKB.
DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006221; P:pyrimidine nucleotide biosynthetic process; NAS:UniProtKB.
DR GO; GO:0009156; P:ribonucleoside monophosphate biosynthetic process; IEA:InterPro.
DR GO; GO:0034418; P:urate biosynthetic process; IMP:UniProtKB.
DR InterPro; IPR000842; PRib_PP_synth_CS.
DR InterPro; IPR005946; Rib-P_diPkinase.
DR Pfam; PF14572; Pribosyl_synth; 1.
DR TIGRFAMs; TIGR01251; ribP_PPkin; 1.
DR PROSITE; PS00114; PRPP_SYNTHASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Charcot-Marie-Tooth disease;
KW Complete proteome; Deafness; Direct protein sequencing;
KW Disease mutation; Gout; Kinase; Magnesium; Mental retardation;
KW Metal-binding; Neuropathy; Non-syndromic deafness;
KW Nucleotide biosynthesis; Nucleotide-binding; Polymorphism;
KW Reference proteome; Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 318 Ribose-phosphate pyrophosphokinase 1.
FT /FTId=PRO_0000141071.
FT NP_BIND 96 101 ATP.
FT REGION 212 227 Binding of phosphoribosylpyrophosphate
FT (Potential).
FT METAL 128 128 Magnesium (Potential).
FT METAL 130 130 Magnesium (Potential).
FT METAL 139 139 Magnesium (Potential).
FT METAL 143 143 Magnesium (Potential).
FT BINDING 130 130 ATP.
FT VARIANT 43 43 E -> D (in CMTX5).
FT /FTId=VAR_036941.
FT VARIANT 52 52 D -> H (in PRPS1 superactivity).
FT /FTId=VAR_016044.
FT VARIANT 65 65 D -> N (in DFNX1).
FT /FTId=VAR_063522.
FT VARIANT 87 87 A -> T (in DFNX1).
FT /FTId=VAR_063523.
FT VARIANT 114 114 N -> S (in PRPS1 superactivity).
FT /FTId=VAR_004163.
FT VARIANT 115 115 M -> T (in CMTX5).
FT /FTId=VAR_036942.
FT VARIANT 129 129 L -> I (in PRPS1 superactivity).
FT /FTId=VAR_016045.
FT VARIANT 133 133 Q -> P (in ARTS).
FT /FTId=VAR_036943.
FT VARIANT 152 152 L -> P (in ARTS).
FT /FTId=VAR_036944.
FT VARIANT 183 183 D -> H (in PRPS1 superactivity).
FT /FTId=VAR_004164.
FT VARIANT 190 190 A -> V (in PRPS1 superactivity).
FT /FTId=VAR_016046.
FT VARIANT 193 193 H -> Q (in PRPS1 superactivity).
FT /FTId=VAR_016047.
FT VARIANT 203 203 D -> H (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036593.
FT VARIANT 219 219 V -> G (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036594.
FT VARIANT 231 231 H -> D (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036595.
FT VARIANT 290 290 I -> T (in DFNX1).
FT /FTId=VAR_063524.
FT VARIANT 306 306 G -> R (in DFNX1).
FT /FTId=VAR_063525.
FT MUTAGEN 132 132 S->A: Reduces catalytic activity.
FT MUTAGEN 132 132 S->F: No effect on catalytic activity.
FT MUTAGEN 144 144 N->H: No effect on catalytic activity.
FT MUTAGEN 146 146 Y->F: No effect on catalytic activity.
FT MUTAGEN 146 146 Y->M: Reduces catalytic activity.
FT STRAND 4 8
FT HELIX 14 22
FT STRAND 30 34
FT STRAND 36 38
FT STRAND 40 44
FT STRAND 52 56
FT HELIX 63 79
FT STRAND 83 91
FT TURN 93 96
FT STRAND 101 104
FT HELIX 108 119
FT STRAND 122 128
FT HELIX 132 137
FT STRAND 142 145
FT HELIX 148 158
FT HELIX 162 164
FT STRAND 166 171
FT HELIX 172 174
FT HELIX 175 185
FT STRAND 188 194
FT STRAND 205 209
FT STRAND 214 225
FT HELIX 227 238
FT STRAND 242 251
FT HELIX 257 263
FT STRAND 267 272
FT HELIX 278 282
FT STRAND 287 290
FT HELIX 293 305
FT HELIX 310 313
SQ SEQUENCE 318 AA; 34834 MW; 46D017E969908BA0 CRC64;
MPNIKIFSGS SHQDLSQKIA DRLGLELGKV VTKKFSNQET CVEIGESVRG EDVYIVQSGC
GEINDNLMEL LIMINACKIA SASRVTAVIP CFPYARQDKK DKSRAPISAK LVANMLSVAG
ADHIITMDLH ASQIQGFFDI PVDNLYAEPA VLKWIRENIS EWRNCTIVSP DAGGAKRVTS
IADRLNVDFA LIHKERKKAN EVDRMVLVGD VKDRVAILVD DMADTCGTIC HAADKLLSAG
ATRVYAILTH GIFSGPAISR INNACFEAVV VTNTIPQEDK MKHCSKIQVI DISMILAEAI
RRTHNGESVS YLFSHVPL
//
MIM
300661
*RECORD*
*FIELD* NO
300661
*FIELD* TI
#300661 PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
;;PRPS1 SUPERACTIVITY
read moreGOUT, PRPS-RELATED, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the phenotype is
caused by mutations in the gene encoding phosphoribosylpyrophosphate
synthetase I (PRPS1; 311850) that result in increased enzyme activity.
X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) is an
allelic disorder resulting from decreased enzyme activity. Affected
individuals have neurologic symptoms, including sensorineural deafness.
Another allelic disorder, Arts syndrome (301835), results from loss of
PRPS1 activity and has a severe neurologic phenotype including mental
retardation, early-onset hypotonia, and susceptibility to infections.
DESCRIPTION
Phosphoribosylpyrophosphate synthetase I superactivity is an X-linked
inborn error of metabolism in which increased enzyme activity is
associated with hyperuricemia and gout. Some affected individuals have
neurodevelopmental abnormalities, particularly sensorineural deafness
(Becker et al., 1988; Roessler et al., 1993).
Although different kinetic defects affecting the PRPS1 enzyme have been
identified in this disorder, the common pathway involves increased
synthesis of phosphoribosylpyrophosphate (PRPP), which leads to
increased uric acid and purine production (Becker, 2001).
CLINICAL FEATURES
Sperling et al. (1972, 1973) and Zoref et al. (1975, 1977) described a
familial disorder characterized by early-adult onset of excessive purine
production, gout, and uric acid urolithiasis associated with
hyperuricemia and hyperuricosuria. The PRPS1 enzyme activity was
described as 'superactive,' showing increased de novo synthesis of
purine nucleotides. PRPS1 activity in red cells and cultured skin
fibroblasts was resistant to feedback inhibition by guanosine
diphosphate (GDP) and adenosine diphosphate (ADP). Fibroblast cultures
were homogeneous for the mutant enzyme in affected males, whereas
unaffected females showed mutant and normal activity. The pattern of
inheritance was X-linked recessive.
Becker et al. (1980) provided follow-up studies of a family reported by
Nyhan et al. (1969) in which a boy had hyperuricemia, mental
retardation, and sensorineural deafness from infancy associated with
PRPS1 superactivity. His affected mother had gout, uric acid
urolithiasis, and significant hearing loss. Fibroblast studies of this
patient and his mother indicated that the mutant enzyme had both
regulatory and catalytic defects. The enzyme showed 4- to 5-fold greater
than normal resistance to feedback inhibition and, in addition,
increased maximal velocity of the enzyme reaction. The son was
hemizygous, and his mother heterozygous, for the defect.
Simmonds et al. (1982) reported a 3-year-old boy with hypotonia,
locomotor delay, and high frequency hearing loss associated with purine
hyperactivity. The same disorder was probably present in 2 brothers who
died in early childhood. The mother also showed hyperuricemia, purine
overproduction, and sensorineural deafness from infancy. Severe
depletion of red cell nicotinamide adenine dinucleotide (NAD) and GTP
appeared to be associated with the neurologic abnormalities. Simmonds et
al. (1982) referred to the report of Rosenberg et al. (1970) in which 5
family members had ataxia, deafness, hyperuricemia, and renal
insufficiency. Serum urate levels were elevated in other members of the
kindred who did not have renal insufficiency, indicating that the
hyperuricemia was not secondary to renal disease. Red cell
hypoxanthine-guanine phosphoribosyltransferase (HPRT1; 308000) levels
were normal. The pedigree was consistent with X-linked inheritance with
full expression in some females and incomplete expression in others.
Riccardi (1974) studied the same family and concluded that X-linked
dominant inheritance was unlikely because males seemed to be no more
severely affected on the average than females.
Becker et al. (1988) reported a Spanish mother and son with PRPS1
superactivity. The 8-year-old boy had tophaceous gout, purine nucleotide
and uric acid overproduction, and sensorineural deafness; his
27-year-old mother had gout. Fibroblast studies showed that the kinetic
basis of superactivity in this family was resistance to purine
nucleotide inhibition of enzyme activity. The boy was hemizygous, and
his mother heterozygous, for the defect.
Christen et al. (1992) described a family with hyperuricemia and
aberrant PRPS activity affecting the mother and 2 sons. Hypertonia and
hyperuricemia were recognized in the mother at the age of 20 years; she
later developed gouty arthritis. Her 2 sons were born prematurely by
cesarean section. Gestational diabetes mellitus was diagnosed during the
pregnancy with the first affected son, and both sons were diagnosed as
having neonatal diabetes mellitus requiring insulin treatment through
early childhood. Both boys showed growth retardation, mental and motor
retardation with absent development of speech, muscular hypotonia
(especially during the first year of life), cerebellar ataxia, and
dysmetria, polyneuropathy with areflexia, and atrophy of the lower legs.
All 3 had facial stigmata suggestive of a genetic syndrome, including
triangular face with prominent forehead, epicanthus, hypotelorism,
beaked nose, broad mouth, and hyperopia. Electroneurography in both boys
demonstrated a progressive axonal neuropathy with demyelinization.
Hearing was not impaired in any of the three. Crystals of urate could be
seen in the diapers and on the tip of the penis in both boys, but both
had normal renal function. Findings in fibroblasts and lymphoblasts of
both boys suggested superactivity of PRPS due to resistance of the
enzyme to nucleotide feedback.
Moran et al. (2012) described a patient with PRPS1 superactivity as well
as features of Arts syndrome (301835), a developmental disorder also
caused by mutations in the PRPS1 gene. Laboratory studies showed
increased serum uric acid and increased urinary hypoxanthine consistent
with PRPS1 superactivity, but he did not have gout. He had developmental
delay, hypotonia, areflexia, motor neuropathy, sensorineural hearing
loss, and a Chiari I malformation. In addition, he had recurrent
infections and early death at age 27 months from infection, consistent
with Arts syndrome. A maternal uncle with similar symptoms had died of
pneumonia at age 2.
INHERITANCE
Becker et al. (1973) concluded that the PRPS mutation that led to gout
in a family they studied was autosomal dominant, but in later studies
(Yen et al., 1978) presented evidence for X-linkage: a daughter of an
affected male had activity of the enzyme in fibroblasts intermediate
between the normal and that of affected males. Furthermore, the affected
mother showed 2 electrophoretically distinct bands of PRPS1 activity: 1
corresponding to the normal single band and 1 corresponding to the
single band of affected males. However, erythrocytes and lymphocytes in
the female showed increased synthetase activity of the same magnitude as
that in affected males. This suggested nonrandom lyonization in
progenitor cells or, more likely, selection against the cells with the
wildtype X chromosome as the active one.
MOLECULAR GENETICS
In a boy with hyperuricemia, sensorineural deafness, ataxia, and
secondary renal insufficiency associated with PRPS1 superactivity
reported by Becker et al. (1986), Roessler et al. (1991, 1993)
identified mutation in the PRPS1 gene (311850.0001). Biochemical studies
in fibroblasts were consistent with PRPS superactivity and purine
nucleotide feedback-resistance.
In a son and mother with PRPS1 superactivity reported by Becker et al.
(1980), Roessler et al. (1993) identified a mutation in the PRPS1 gene
(311850.0002). Both had sensorineural hearing loss since infancy.
In a man with PRPS1 superactivity associated only with early-onset gout
(Zoref et al., 1975), Becker et al. (1995) identified a hemizygous
mutation in the PRPS1 gene (311850.0003).
In a patient with a complex phenotype comprising Arts syndrome and PRPS1
superactivity, Moran et al. (2012) detected a missense mutation in the
transversion in exon 4 of the PRPS1 gene (V142L; 311850.0017).
PATHOGENESIS
- Superactivity Due to Defective Allosteric Regulation of
PRPS1
Becker et al. (1996) stated that defective allosteric regulation of
PRPS1 activity by purine nucleotide inhibitors (such as ADP and GDP) and
by the activator P(i) characterizes one kinetically defined class of
superactive PRS that result from point mutations in the PRPS1 gene
(Becker et al., 1995; Becker et al., 1996).
- Catalytic Superactivity of PRPS1
Becker et al. (1973, 1973) reported 2 brothers with gout and excessive
purine synthesis associated with increased intrinsic catalytic activity
of the PRPS enzyme.
Becker et al. (1986) studied fibroblasts and red cells from 4 unrelated
males with early-adult onset of hyperuricemia, gout, and uric acid
overproduction. The kinetic basis of enzyme superactivity in all
patients was determined to be increased maximal reaction velocity.
Affinities for substrate activators and responsiveness to inhibitors
were normal, and all had increased phosphoribosylpyrophosphate
concentration and generation. Cultured fibroblasts of female relatives
of 2 patients showed evidence of heterozygosity as measured by enzyme
activities and rates of purine synthesis. Altered physical properties of
the superactive enzymes suggested that several distinctive variants may
be represented.
Becker et al. (1996) noted that in a second and more frequently
encountered class of PRPS superactivity, regulation of enzyme activity
by nucleotide inhibitors is normal, as are affinities for substrates and
activators such as Mg(2+) and P(i). This so-called inherited 'catalytic'
superactivity was unassociated with alteration in the translated
sequences of either PRPS1 or PRPS2 cDNA, which is in contrast to PRPS
superactivity associated with defective allosteric regulatory
properties. Rather, catalytic overactivity of PRPS appeared to reflect
increased intracellular concentrations of the normal PRPS1 isoform.
Accumulating increases in levels of PRPS1 transcript with entirely
normal sequence in cells from affected individuals suggested derangement
of a pretranslational mechanism regulating the expression of PRPS1 in
catalytic superactivity of PRPS.
*FIELD* SA
De Vries and Sperling (1973); Takeuchi et al. (1981); Zoref et al.
(1976)
*FIELD* RF
1. Becker, M. A.: Hyperuricemia and Gout.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. New York: McGraw-Hill (8th
ed.): 2001. P. 2625.
2. Becker, M. A.; Kostel, P. J.; Meyer, L. J.; Seegmiller, J. E.:
Human phosphoribosylpyrophosphate synthetase: increased enzyme specific
activity in a family with gout and excessive purine synthesis. Proc.
Nat. Acad. Sci. 70: 2749-2752, 1973.
3. Becker, M. A.; Losman, M. J.; Rosenberg, A. L.; Mehlman, I.; Levinson,
D. J.; Holmes, E. W.: Phosphoribosylpyrophosphate synthetase superactivity:
a study of five patients with catalytic defects in the enzyme. Arthritis
Rheum. 29: 880-888, 1986.
4. Becker, M. A.; Losman, M. J.; Wilson, J.; Simmonds, H. A.: Superactivity
of human phosphoribosyl pyrophosphate synthetase due to altered regulation
by nucleotide inhibitors and inorganic phosphate. Biochim. Biophys.
Acta 882: 168-176, 1986.
5. Becker, M. A.; Meyer, L. J.; Seegmiller, J. E.: Gout with purine
overproduction due to increased phosphoribosylphosphate synthetase
activity. Am. J. Med. 55: 232-242, 1973.
6. Becker, M. A.; Meyer, L. J.; Wood, A. W.; Seegmiller, J. E.: Purine
overproduction in man associated with increased phosphoribosylpyrophosphate
synthetase activity. Science 179: 1123-1126, 1973.
7. Becker, M. A.; Puig, J. G.; Mateos, F. A.; Jimenez, M. L.; Kim,
M.; Simmonds, H. A.: Inherited superactivity of phosphoribosylpyrophosphate
synthetase: association of uric acid overproduction and sensorineural
deafness. Am. J. Med. 85: 383-390, 1988.
8. Becker, M. A.; Raivio, K. O.; Bakay, B.; Adams, W. B.; Nyhan, W.
L.: Variant human phosphoribosylpyrophosphate synthetase altered
in regulatory and catalytic functions. J. Clin. Invest. 65: 109-120,
1980.
9. Becker, M. A.; Smith, P. R.; Taylor, W.; Mustafi, R.; Switzer,
R. L.: The genetic and functional basis of purine nucleotide feedback-resistant
phosphoribosylpyrophosphate synthetase superactivity. J. Clin. Invest. 96:
2133-2141, 1995.
10. Becker, M. A.; Taylor, W.; Smith, P. R.; Ahmed, M.: Overexpression
of the normal phosphoribosylpyrophosphate synthetase 1 isoform underlies
catalytic superactivity of human phosphoribosylpyrophosphate synthetase. J.
Biol. Chem. 271: 19894-19899, 1996.
11. Christen, H.-J.; Hanefeld, F.; Duley, J. A.; Simmonds, H. A.:
Distinct neurological syndrome in two brothers with hyperuricaemia.
(Letter) Lancet 340: 1167-1168, 1992.
12. De Vries, A.; Sperling, O.: Familial gouty malignant uric acid
lithiasis due to mutant phosphoribosylpyrophosphatase synthetase. Der
Urologe 12: 153-157, 1973.
13. Moran, R.; Kuilenburg, A. B. P.; Duley, J.; Nabuurs, S. B.; Retno-Fitri,
A.; Christodoulou, J.; Roelofsen, J.; Yntema, H. G.; Friedman, N.
R.; van Bokhoven, H.; de Brouwer, A. P. M.: Phosphoribosylpyrophosphate
synthetase superactivity and recurrent infections is caused by a p.val142-to-leu
mutation in PRS-I. Am. J. Med. Genet. 158A: 455-460, 2012.
14. Nyhan, W. L.; James, J. A.; Teberg, A. J.; Sweetman, L.; Nelson,
L. G.: A new disorder of purine metabolism with behavioral manifestations. J.
Pediat. 74: 20-27, 1969.
15. Riccardi, V. M.: Personal Communication. Denver, Colo. 1974.
16. Roessler, B. J.; Nosal, J. M.; Smith, P. R.; Heidler, S. A.; Palella,
T. D.; Switzer, R. L.; Becker, M. A.: Human X-linked phosphoribosylpyrophosphate
synthetase superactivity is associated with distinct point mutations
in the PRPS1 gene. J. Biol. Chem. 268: 26476-26481, 1993.
17. Roessler, B. J.; Palella, T. D.; Heidler, S.; Becker, M. A.:
Identification of distinct PRPS1 mutations in two patients with X-linked
phosphoribosylpyrophosphate synthetase superactivity. (Abstract) Clin.
Res. 39: 267A, 1991.
18. Rosenberg, A. L.; Bergstrom, L.; Troost, B. T.; Bartholomew, B.
A.: Hyperuricemia and neurologic deficits: a family study. New Eng.
J. Med. 282: 992-997, 1970.
19. Simmonds, H. A.; Webster, D. R.; Wilson, J.; Lingham, S.: An
X-linked syndrome characterised by hyperuricaemia, deafness, and neurodevelopmental
abnormalities. Lancet 320: 68-70, 1982. Note: Originally Volume
2.
20. Sperling, O.; Eliam, G.; Persky-Brosh, S.; De Vries, A.: Accelerated
erythrocyte 5-phosphoribosyl-1-pyrophosphate synthesis: a familial
abnormality associated with excessive uric acid production and gout. Biochem.
Med. 6: 310-316, 1972.
21. Sperling, O.; Persky-Brosh, S.; Boer, P.; De Vries, A.: Human
erythrocyte phosphoribosylpyrophosphate synthetase mutationally altered
in regulatory properties. Biochem. Med. 7: 389-395, 1973.
22. Takeuchi, F.; Hanaoka, F.; Yano, E.; Yamada, M.; Horiuchi, Y.;
Akaoka, I.: The mode of genetic transmission of a gouty family with
increased phosphoribosylpyrophosphate synthetase activity. Hum. Genet. 58:
322-330, 1981.
23. Yen, R. C. K.; Adams, W. B.; Lazar, C.; Becker, M. A.: Evidence
for X-linkage of human phosphoribosylpyrophosphate synthetase. Proc.
Nat. Acad. Sci. 75: 482-485, 1978.
24. Zoref, E.; De Vries, A.; Sperling, O.: Mutant feedback-resistant
phosphoribosylpyrophosphate synthetase associated with purine overproduction
and gout: phosphoribosylpyrophosphate and purine metabolism in cultured
fibroblasts. J. Clin. Invest. 56: 1093-1099, 1975.
25. Zoref, E.; De Vries, A.; Sperling, O.: Metabolic cooperation
between human fibroblasts with normal and with mutant superactive
phosphoribosylpyrophosphate synthetase. Nature 260: 787-788, 1976.
26. Zoref, E.; De Vries, A.; Sperling, O.: Evidence for X-linkage
of phosphoribosylpyrophosphate synthetase in man: studies with cultured
fibroblasts from a gouty family with mutant feedback-resistant enzyme. Hum.
Hered. 27: 73-80, 1977.
*FIELD* CS
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Ears];
Sensorineural hearing loss (early-onset form)
GENITOURINARY:
[Kidneys];
Uric acid urolithiasis;
Secondary renal insufficiency
SKELETAL:
Gout;
Gouty arthritis
NEUROLOGIC:
[Central nervous system];
Neurodevelopmental impairment (early-onset form);
Hypotonia (early-onset form);
Locomotor delay (early-onset form);
Mental retardation (early-onset form);
Ataxia (early-onset form)
METABOLIC FEATURES:
Overproduction of uric acid and purines
LABORATORY ABNORMALITIES:
Hyperuricemia;
Hyperuricosuria;
Increased activity of the PRPP synthetase 1 enzyme
MISCELLANEOUS:
Two main phenotypes, early-onset with neurologic defects and early-adult
onset with gout;
Heterozygous females may have gout and/or sensorineural deafness
MOLECULAR BASIS:
Caused by mutation in the phosphoribosylpyrophosphate synthetase I
gene (PRPS1, 311850.0001)
*FIELD* CD
Cassandra L. Kniffin: 8/15/2007
*FIELD* ED
joanna: 09/21/2007
joanna: 8/27/2007
ckniffin: 8/16/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 8/16/2007
*FIELD* CD
Cassandra L. Kniffin: 8/13/2007
*FIELD* ED
alopez: 04/20/2012
alopez: 4/12/2012
terry: 4/10/2012
ckniffin: 4/9/2012
terry: 4/9/2009
alopez: 8/22/2007
carol: 8/17/2007
ckniffin: 8/16/2007
*RECORD*
*FIELD* NO
300661
*FIELD* TI
#300661 PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
;;PRPS1 SUPERACTIVITY
read moreGOUT, PRPS-RELATED, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the phenotype is
caused by mutations in the gene encoding phosphoribosylpyrophosphate
synthetase I (PRPS1; 311850) that result in increased enzyme activity.
X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) is an
allelic disorder resulting from decreased enzyme activity. Affected
individuals have neurologic symptoms, including sensorineural deafness.
Another allelic disorder, Arts syndrome (301835), results from loss of
PRPS1 activity and has a severe neurologic phenotype including mental
retardation, early-onset hypotonia, and susceptibility to infections.
DESCRIPTION
Phosphoribosylpyrophosphate synthetase I superactivity is an X-linked
inborn error of metabolism in which increased enzyme activity is
associated with hyperuricemia and gout. Some affected individuals have
neurodevelopmental abnormalities, particularly sensorineural deafness
(Becker et al., 1988; Roessler et al., 1993).
Although different kinetic defects affecting the PRPS1 enzyme have been
identified in this disorder, the common pathway involves increased
synthesis of phosphoribosylpyrophosphate (PRPP), which leads to
increased uric acid and purine production (Becker, 2001).
CLINICAL FEATURES
Sperling et al. (1972, 1973) and Zoref et al. (1975, 1977) described a
familial disorder characterized by early-adult onset of excessive purine
production, gout, and uric acid urolithiasis associated with
hyperuricemia and hyperuricosuria. The PRPS1 enzyme activity was
described as 'superactive,' showing increased de novo synthesis of
purine nucleotides. PRPS1 activity in red cells and cultured skin
fibroblasts was resistant to feedback inhibition by guanosine
diphosphate (GDP) and adenosine diphosphate (ADP). Fibroblast cultures
were homogeneous for the mutant enzyme in affected males, whereas
unaffected females showed mutant and normal activity. The pattern of
inheritance was X-linked recessive.
Becker et al. (1980) provided follow-up studies of a family reported by
Nyhan et al. (1969) in which a boy had hyperuricemia, mental
retardation, and sensorineural deafness from infancy associated with
PRPS1 superactivity. His affected mother had gout, uric acid
urolithiasis, and significant hearing loss. Fibroblast studies of this
patient and his mother indicated that the mutant enzyme had both
regulatory and catalytic defects. The enzyme showed 4- to 5-fold greater
than normal resistance to feedback inhibition and, in addition,
increased maximal velocity of the enzyme reaction. The son was
hemizygous, and his mother heterozygous, for the defect.
Simmonds et al. (1982) reported a 3-year-old boy with hypotonia,
locomotor delay, and high frequency hearing loss associated with purine
hyperactivity. The same disorder was probably present in 2 brothers who
died in early childhood. The mother also showed hyperuricemia, purine
overproduction, and sensorineural deafness from infancy. Severe
depletion of red cell nicotinamide adenine dinucleotide (NAD) and GTP
appeared to be associated with the neurologic abnormalities. Simmonds et
al. (1982) referred to the report of Rosenberg et al. (1970) in which 5
family members had ataxia, deafness, hyperuricemia, and renal
insufficiency. Serum urate levels were elevated in other members of the
kindred who did not have renal insufficiency, indicating that the
hyperuricemia was not secondary to renal disease. Red cell
hypoxanthine-guanine phosphoribosyltransferase (HPRT1; 308000) levels
were normal. The pedigree was consistent with X-linked inheritance with
full expression in some females and incomplete expression in others.
Riccardi (1974) studied the same family and concluded that X-linked
dominant inheritance was unlikely because males seemed to be no more
severely affected on the average than females.
Becker et al. (1988) reported a Spanish mother and son with PRPS1
superactivity. The 8-year-old boy had tophaceous gout, purine nucleotide
and uric acid overproduction, and sensorineural deafness; his
27-year-old mother had gout. Fibroblast studies showed that the kinetic
basis of superactivity in this family was resistance to purine
nucleotide inhibition of enzyme activity. The boy was hemizygous, and
his mother heterozygous, for the defect.
Christen et al. (1992) described a family with hyperuricemia and
aberrant PRPS activity affecting the mother and 2 sons. Hypertonia and
hyperuricemia were recognized in the mother at the age of 20 years; she
later developed gouty arthritis. Her 2 sons were born prematurely by
cesarean section. Gestational diabetes mellitus was diagnosed during the
pregnancy with the first affected son, and both sons were diagnosed as
having neonatal diabetes mellitus requiring insulin treatment through
early childhood. Both boys showed growth retardation, mental and motor
retardation with absent development of speech, muscular hypotonia
(especially during the first year of life), cerebellar ataxia, and
dysmetria, polyneuropathy with areflexia, and atrophy of the lower legs.
All 3 had facial stigmata suggestive of a genetic syndrome, including
triangular face with prominent forehead, epicanthus, hypotelorism,
beaked nose, broad mouth, and hyperopia. Electroneurography in both boys
demonstrated a progressive axonal neuropathy with demyelinization.
Hearing was not impaired in any of the three. Crystals of urate could be
seen in the diapers and on the tip of the penis in both boys, but both
had normal renal function. Findings in fibroblasts and lymphoblasts of
both boys suggested superactivity of PRPS due to resistance of the
enzyme to nucleotide feedback.
Moran et al. (2012) described a patient with PRPS1 superactivity as well
as features of Arts syndrome (301835), a developmental disorder also
caused by mutations in the PRPS1 gene. Laboratory studies showed
increased serum uric acid and increased urinary hypoxanthine consistent
with PRPS1 superactivity, but he did not have gout. He had developmental
delay, hypotonia, areflexia, motor neuropathy, sensorineural hearing
loss, and a Chiari I malformation. In addition, he had recurrent
infections and early death at age 27 months from infection, consistent
with Arts syndrome. A maternal uncle with similar symptoms had died of
pneumonia at age 2.
INHERITANCE
Becker et al. (1973) concluded that the PRPS mutation that led to gout
in a family they studied was autosomal dominant, but in later studies
(Yen et al., 1978) presented evidence for X-linkage: a daughter of an
affected male had activity of the enzyme in fibroblasts intermediate
between the normal and that of affected males. Furthermore, the affected
mother showed 2 electrophoretically distinct bands of PRPS1 activity: 1
corresponding to the normal single band and 1 corresponding to the
single band of affected males. However, erythrocytes and lymphocytes in
the female showed increased synthetase activity of the same magnitude as
that in affected males. This suggested nonrandom lyonization in
progenitor cells or, more likely, selection against the cells with the
wildtype X chromosome as the active one.
MOLECULAR GENETICS
In a boy with hyperuricemia, sensorineural deafness, ataxia, and
secondary renal insufficiency associated with PRPS1 superactivity
reported by Becker et al. (1986), Roessler et al. (1991, 1993)
identified mutation in the PRPS1 gene (311850.0001). Biochemical studies
in fibroblasts were consistent with PRPS superactivity and purine
nucleotide feedback-resistance.
In a son and mother with PRPS1 superactivity reported by Becker et al.
(1980), Roessler et al. (1993) identified a mutation in the PRPS1 gene
(311850.0002). Both had sensorineural hearing loss since infancy.
In a man with PRPS1 superactivity associated only with early-onset gout
(Zoref et al., 1975), Becker et al. (1995) identified a hemizygous
mutation in the PRPS1 gene (311850.0003).
In a patient with a complex phenotype comprising Arts syndrome and PRPS1
superactivity, Moran et al. (2012) detected a missense mutation in the
transversion in exon 4 of the PRPS1 gene (V142L; 311850.0017).
PATHOGENESIS
- Superactivity Due to Defective Allosteric Regulation of
PRPS1
Becker et al. (1996) stated that defective allosteric regulation of
PRPS1 activity by purine nucleotide inhibitors (such as ADP and GDP) and
by the activator P(i) characterizes one kinetically defined class of
superactive PRS that result from point mutations in the PRPS1 gene
(Becker et al., 1995; Becker et al., 1996).
- Catalytic Superactivity of PRPS1
Becker et al. (1973, 1973) reported 2 brothers with gout and excessive
purine synthesis associated with increased intrinsic catalytic activity
of the PRPS enzyme.
Becker et al. (1986) studied fibroblasts and red cells from 4 unrelated
males with early-adult onset of hyperuricemia, gout, and uric acid
overproduction. The kinetic basis of enzyme superactivity in all
patients was determined to be increased maximal reaction velocity.
Affinities for substrate activators and responsiveness to inhibitors
were normal, and all had increased phosphoribosylpyrophosphate
concentration and generation. Cultured fibroblasts of female relatives
of 2 patients showed evidence of heterozygosity as measured by enzyme
activities and rates of purine synthesis. Altered physical properties of
the superactive enzymes suggested that several distinctive variants may
be represented.
Becker et al. (1996) noted that in a second and more frequently
encountered class of PRPS superactivity, regulation of enzyme activity
by nucleotide inhibitors is normal, as are affinities for substrates and
activators such as Mg(2+) and P(i). This so-called inherited 'catalytic'
superactivity was unassociated with alteration in the translated
sequences of either PRPS1 or PRPS2 cDNA, which is in contrast to PRPS
superactivity associated with defective allosteric regulatory
properties. Rather, catalytic overactivity of PRPS appeared to reflect
increased intracellular concentrations of the normal PRPS1 isoform.
Accumulating increases in levels of PRPS1 transcript with entirely
normal sequence in cells from affected individuals suggested derangement
of a pretranslational mechanism regulating the expression of PRPS1 in
catalytic superactivity of PRPS.
*FIELD* SA
De Vries and Sperling (1973); Takeuchi et al. (1981); Zoref et al.
(1976)
*FIELD* RF
1. Becker, M. A.: Hyperuricemia and Gout.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. New York: McGraw-Hill (8th
ed.): 2001. P. 2625.
2. Becker, M. A.; Kostel, P. J.; Meyer, L. J.; Seegmiller, J. E.:
Human phosphoribosylpyrophosphate synthetase: increased enzyme specific
activity in a family with gout and excessive purine synthesis. Proc.
Nat. Acad. Sci. 70: 2749-2752, 1973.
3. Becker, M. A.; Losman, M. J.; Rosenberg, A. L.; Mehlman, I.; Levinson,
D. J.; Holmes, E. W.: Phosphoribosylpyrophosphate synthetase superactivity:
a study of five patients with catalytic defects in the enzyme. Arthritis
Rheum. 29: 880-888, 1986.
4. Becker, M. A.; Losman, M. J.; Wilson, J.; Simmonds, H. A.: Superactivity
of human phosphoribosyl pyrophosphate synthetase due to altered regulation
by nucleotide inhibitors and inorganic phosphate. Biochim. Biophys.
Acta 882: 168-176, 1986.
5. Becker, M. A.; Meyer, L. J.; Seegmiller, J. E.: Gout with purine
overproduction due to increased phosphoribosylphosphate synthetase
activity. Am. J. Med. 55: 232-242, 1973.
6. Becker, M. A.; Meyer, L. J.; Wood, A. W.; Seegmiller, J. E.: Purine
overproduction in man associated with increased phosphoribosylpyrophosphate
synthetase activity. Science 179: 1123-1126, 1973.
7. Becker, M. A.; Puig, J. G.; Mateos, F. A.; Jimenez, M. L.; Kim,
M.; Simmonds, H. A.: Inherited superactivity of phosphoribosylpyrophosphate
synthetase: association of uric acid overproduction and sensorineural
deafness. Am. J. Med. 85: 383-390, 1988.
8. Becker, M. A.; Raivio, K. O.; Bakay, B.; Adams, W. B.; Nyhan, W.
L.: Variant human phosphoribosylpyrophosphate synthetase altered
in regulatory and catalytic functions. J. Clin. Invest. 65: 109-120,
1980.
9. Becker, M. A.; Smith, P. R.; Taylor, W.; Mustafi, R.; Switzer,
R. L.: The genetic and functional basis of purine nucleotide feedback-resistant
phosphoribosylpyrophosphate synthetase superactivity. J. Clin. Invest. 96:
2133-2141, 1995.
10. Becker, M. A.; Taylor, W.; Smith, P. R.; Ahmed, M.: Overexpression
of the normal phosphoribosylpyrophosphate synthetase 1 isoform underlies
catalytic superactivity of human phosphoribosylpyrophosphate synthetase. J.
Biol. Chem. 271: 19894-19899, 1996.
11. Christen, H.-J.; Hanefeld, F.; Duley, J. A.; Simmonds, H. A.:
Distinct neurological syndrome in two brothers with hyperuricaemia.
(Letter) Lancet 340: 1167-1168, 1992.
12. De Vries, A.; Sperling, O.: Familial gouty malignant uric acid
lithiasis due to mutant phosphoribosylpyrophosphatase synthetase. Der
Urologe 12: 153-157, 1973.
13. Moran, R.; Kuilenburg, A. B. P.; Duley, J.; Nabuurs, S. B.; Retno-Fitri,
A.; Christodoulou, J.; Roelofsen, J.; Yntema, H. G.; Friedman, N.
R.; van Bokhoven, H.; de Brouwer, A. P. M.: Phosphoribosylpyrophosphate
synthetase superactivity and recurrent infections is caused by a p.val142-to-leu
mutation in PRS-I. Am. J. Med. Genet. 158A: 455-460, 2012.
14. Nyhan, W. L.; James, J. A.; Teberg, A. J.; Sweetman, L.; Nelson,
L. G.: A new disorder of purine metabolism with behavioral manifestations. J.
Pediat. 74: 20-27, 1969.
15. Riccardi, V. M.: Personal Communication. Denver, Colo. 1974.
16. Roessler, B. J.; Nosal, J. M.; Smith, P. R.; Heidler, S. A.; Palella,
T. D.; Switzer, R. L.; Becker, M. A.: Human X-linked phosphoribosylpyrophosphate
synthetase superactivity is associated with distinct point mutations
in the PRPS1 gene. J. Biol. Chem. 268: 26476-26481, 1993.
17. Roessler, B. J.; Palella, T. D.; Heidler, S.; Becker, M. A.:
Identification of distinct PRPS1 mutations in two patients with X-linked
phosphoribosylpyrophosphate synthetase superactivity. (Abstract) Clin.
Res. 39: 267A, 1991.
18. Rosenberg, A. L.; Bergstrom, L.; Troost, B. T.; Bartholomew, B.
A.: Hyperuricemia and neurologic deficits: a family study. New Eng.
J. Med. 282: 992-997, 1970.
19. Simmonds, H. A.; Webster, D. R.; Wilson, J.; Lingham, S.: An
X-linked syndrome characterised by hyperuricaemia, deafness, and neurodevelopmental
abnormalities. Lancet 320: 68-70, 1982. Note: Originally Volume
2.
20. Sperling, O.; Eliam, G.; Persky-Brosh, S.; De Vries, A.: Accelerated
erythrocyte 5-phosphoribosyl-1-pyrophosphate synthesis: a familial
abnormality associated with excessive uric acid production and gout. Biochem.
Med. 6: 310-316, 1972.
21. Sperling, O.; Persky-Brosh, S.; Boer, P.; De Vries, A.: Human
erythrocyte phosphoribosylpyrophosphate synthetase mutationally altered
in regulatory properties. Biochem. Med. 7: 389-395, 1973.
22. Takeuchi, F.; Hanaoka, F.; Yano, E.; Yamada, M.; Horiuchi, Y.;
Akaoka, I.: The mode of genetic transmission of a gouty family with
increased phosphoribosylpyrophosphate synthetase activity. Hum. Genet. 58:
322-330, 1981.
23. Yen, R. C. K.; Adams, W. B.; Lazar, C.; Becker, M. A.: Evidence
for X-linkage of human phosphoribosylpyrophosphate synthetase. Proc.
Nat. Acad. Sci. 75: 482-485, 1978.
24. Zoref, E.; De Vries, A.; Sperling, O.: Mutant feedback-resistant
phosphoribosylpyrophosphate synthetase associated with purine overproduction
and gout: phosphoribosylpyrophosphate and purine metabolism in cultured
fibroblasts. J. Clin. Invest. 56: 1093-1099, 1975.
25. Zoref, E.; De Vries, A.; Sperling, O.: Metabolic cooperation
between human fibroblasts with normal and with mutant superactive
phosphoribosylpyrophosphate synthetase. Nature 260: 787-788, 1976.
26. Zoref, E.; De Vries, A.; Sperling, O.: Evidence for X-linkage
of phosphoribosylpyrophosphate synthetase in man: studies with cultured
fibroblasts from a gouty family with mutant feedback-resistant enzyme. Hum.
Hered. 27: 73-80, 1977.
*FIELD* CS
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Ears];
Sensorineural hearing loss (early-onset form)
GENITOURINARY:
[Kidneys];
Uric acid urolithiasis;
Secondary renal insufficiency
SKELETAL:
Gout;
Gouty arthritis
NEUROLOGIC:
[Central nervous system];
Neurodevelopmental impairment (early-onset form);
Hypotonia (early-onset form);
Locomotor delay (early-onset form);
Mental retardation (early-onset form);
Ataxia (early-onset form)
METABOLIC FEATURES:
Overproduction of uric acid and purines
LABORATORY ABNORMALITIES:
Hyperuricemia;
Hyperuricosuria;
Increased activity of the PRPP synthetase 1 enzyme
MISCELLANEOUS:
Two main phenotypes, early-onset with neurologic defects and early-adult
onset with gout;
Heterozygous females may have gout and/or sensorineural deafness
MOLECULAR BASIS:
Caused by mutation in the phosphoribosylpyrophosphate synthetase I
gene (PRPS1, 311850.0001)
*FIELD* CD
Cassandra L. Kniffin: 8/15/2007
*FIELD* ED
joanna: 09/21/2007
joanna: 8/27/2007
ckniffin: 8/16/2007
*FIELD* CN
Cassandra L. Kniffin - updated: 8/16/2007
*FIELD* CD
Cassandra L. Kniffin: 8/13/2007
*FIELD* ED
alopez: 04/20/2012
alopez: 4/12/2012
terry: 4/10/2012
ckniffin: 4/9/2012
terry: 4/9/2009
alopez: 8/22/2007
carol: 8/17/2007
ckniffin: 8/16/2007
MIM
301835
*RECORD*
*FIELD* NO
301835
*FIELD* TI
#301835 ARTS SYNDROME; ARTS
;;MENTAL RETARDATION, X-LINKED, SYNDROMIC, ARTS TYPE; MRXSARTS;;
read moreATAXIA, FATAL X-LINKED, WITH DEAFNESS AND LOSS OF VISION;;
MENTAL RETARDATION, X-LINKED, SYNDROMIC 18; MRXS18
*FIELD* TX
A number sign (#) is used with this entry because of evidence that Arts
syndrome is caused by loss-of-function mutations in the PRPS1 gene
(311850).
X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) is an
allelic disorder resulting from decreased enzyme activity. Affected
individuals have neurologic symptoms, including sensorineural deafness.
Another allelic disorder, PRPS-related gout (300661), results from
increased enzyme activity. Some affected patients have neurologic
symptoms, including sensorineural deafness.
DESCRIPTION
Arts syndrome is an X-linked disorder characterized by mental
retardation, early-onset hypotonia, ataxia, delayed motor development,
hearing impairment, and optic atrophy (de Brouwer et al., 2007).
Susceptibility to infections, especially of the upper respiratory tract,
can result in early death.
CLINICAL FEATURES
In 12 boys in 3 generations of a kindred in an X-linked recessive
pattern of inheritance, Arts et al. (1993) described a disorder leading
to death in early childhood. The manifestations were early-onset
floppiness, ataxia, liability to infections, especially of the upper
respiratory tract, deafness, and later, a flaccid tetraplegia and
areflexia. Although 1 boy was still alive at the age of 12 years, 11 had
died before the age of 5 years. The surviving boy required ventilation
at night and was nearly blind due to optic atrophy. In the only patient
in whom the central nervous system (CNS) could be examined at autopsy,
almost complete absence of myelin in the posterior columns of the spinal
cord was found. Among the female carriers, hearing impairment in early
adulthood appeared to be a feature.
Kremer et al. (1996) noted that infections were the cause of death
before the age of 6 years in 11 of the 12 boys reported by Arts et al.
(1993). The oldest patient, then 16 years of age, had become nearly
blind owing to optic atrophy and lived in an institution for the
visually and mentally handicapped. Clinical signs indicated impairment
of the posterior columns, peripheral motor and sensory neurons, and the
second and eighth cranial nerves and/or nuclei. In addition to
perceptive hearing loss, ataxic diplegia, extensor plantar reflexes,
hypotonia, and hyper- or hyporeflexia were thought to be features of the
heterozygous state. Kremer et al. (1996) noted the phenotypic
similarities to the family reported by Schmidley et al. (1987) (301790).
Moran et al. (2012) reported a young boy with a complex phenotype
comprising Arts syndrome and PRPS1 superactivity. He had developmental
delay, hypotonia, areflexia, motor neuropathy, sensorineural hearing
loss, and a Chiari I malformation. Laboratory studies showed increased
serum uric acid and increased urinary hypoxanthine consistent with PRPS1
superactivity, but he did not have gout. In addition, he had recurrent
infections and early death at age 27 months from infection, consistent
with Arts syndrome. A maternal uncle with similar symptoms had died of
pneumonia at age 2.
MAPPING
Using linkage analysis, Kremer et al. (1996) localized the gene (or
genes) responsible for the Arts syndrome phenotype to Xq21.33-q24
between DXS1231 and DXS1001 with a maximum lod score of 6.97. They noted
that the gene encoding proteolipid protein (300401), which codes for 2
myelin proteins of the central nervous system, is located in this region
and should be considered as a candidate gene for the disorder. However,
no mutations were found in the protein-coding part of the gene.
By linkage analysis in a Dutch family and an Australian family, de
Brouwer et al. (2007) mapped the candidate gene to Xq22.1-q24.
MOLECULAR GENETICS
Using oligonucleotide microarray expression profiling in fibroblasts
from 2 probands of a Dutch family with Arts syndrome, de Brouwer et al.
(2007) found reduced expression levels of the PRPS1 gene (311850).
Sequencing of PRPS1 led to the identification of 2 different missense
mutations, L152P (311850.0011) in the Dutch family and Q133P
(311850.0012) in the Australian family. Both mutations resulted in a
loss of PRPS1 activity, as was shown in silico by molecular modeling and
in vitro by enzyme assays in erythrocytes and fibroblasts from patients.
Gain-of-function mutations in PRPS1 result in PRPS-related gout (see
300661). The loss-of-function mutations of PRPS1 likely result in
impaired purine biosynthesis, which was supported by the undetectable
hypoxanthine in urine and the reduced uric acid levels in serum from
patients. De Brouwer et al. (2007) suggested that treatment with
S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy
to replenish low levels of purines. A clinical trial involving the 2
affected Australian brothers was underway. De Brouwer et al. (2010)
reported preliminary results of the 2 Australian brothers with Arts
syndrome, which revealed some improvement of their condition.
In a patient with a complex phenotype comprising Arts syndrome and PRPS1
superactivity, Moran et al. (2012) detected a missense mutation in the
transversion in exon 4 of the PRPS1 gene (V142L; 311850.0017). Both the
mother and grandmother were heterozygous for the mutation. Molecular
modeling predicted that the substitution would disrupt allosteric sites
involved in inhibition of PRPS1, resulting in a gain of enzyme function,
and the ATP-binding site, resulting in a loss of enzyme function.
Patient fibroblasts showed normal PRPP synthetase activity, whereas
erythrocytes showed a loss of enzyme activity, suggesting that the
effect of the V142L mutation on protein activity depends on cell type.
Moran et al. (2012) postulated a gain-of-function effect in
proliferating cells and a loss-of-function effect in postmitotic cells.
The report indicated that PRPS1 missense mutations can cause a
continuous spectrum of features ranging from progressive nonsyndromic
postlingual hearing impairment to uric acid overproduction, neuropathy,
and recurrent infections depending on the functional sites affected.
*FIELD* RF
1. Arts, W. F. M.; Loonen, M. C. B.; Sengers, R. C. A.; Slooff, J.
L.: X-linked ataxia, weakness, deafness, and loss of vision in early
childhood with a fatal course. Ann. Neurol. 33: 535-539, 1993.
2. de Brouwer, A. P. M.; van Bokhoven, H.; Nabuurs, S. B.; Arts, W.
F.; Christodoulou, J.; Duley, J.: PRPS1 mutations: four distinct
syndromes and potential treatment. Am. J. Hum. Genet. 86: 506-518,
2010.
3. de Brouwer, A. P. M.; Williams, K. L.; Duley, J. A.; van Kuilenburg,
A. B. P.; Nabuurs, S. B.; Egmont-Petersen, M.; Lugtenberg, D.; Zoetekouw,
L.; Banning, M. J. G.; Roeffen, M.; Hamel, B. C. J.; Weaving, L.;
Ouvrier, R. A.; Donald, J. A.; Wevers, R. A.; Christodoulou, J.; van
Bokhoven, H.: Arts syndrome is caused by loss-of-function mutations
in PRPS1. Am. J. Hum. Genet. 81: 507-518, 2007.
4. Kremer, H.; Hamel, B. C. J.; van den Helm, B.; Arts, W. F. M.;
de Wijs, I. J.; Sistermans, E. A.; Ropers, H.-H.; Mariman, E. C. M.
: Localization of the gene (or genes) for a syndrome with X-linked
mental retardation, ataxia, weakness, hearing impairment, loss of
vision and a fatal course in early childhood. Hum. Genet. 98: 513-517,
1996.
5. Moran, R.; Kuilenburg, A. B. P.; Duley, J.; Nabuurs, S. B.; Retno-Fitri,
A.; Christodoulou, J.; Roelofsen, J.; Yntema, H. G.; Friedman, N.
R.; van Bokhoven, H.; de Brouwer, A. P. M.: Phosphoribosylpyrophosphate
synthetase superactivity and recurrent infections is caused by a p.val142-to-leu
mutation in PRS-I. Am. J. Med. Genet. 158A: 455-460, 2012.
6. Schmidley, J. W.; Levinsohn, M. W.; Manetto, V.: Infantile X-linked
ataxia and deafness: a new clinicopathologic entity. Neurology 37:
1344-1349, 1987.
*FIELD* CS
INHERITANCE:
X-linked recessive
GROWTH:
[Other];
Poor growth
HEAD AND NECK:
[Ears];
Hearing impairment, sensorineural;
[Eyes];
Optic atrophy;
Loss of vision;
Nystagmus;
[Mouth];
Drooling
RESPIRATORY:
Recurrent respiratory tract infections
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Hypotonia, neonatal;
Muscle weakness, progressive
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Lack of speech;
Ataxia;
Seizures;
Flaccid tetraplegia;
Hyperreflexia (less common);
Absence of myelin in the posterior column of the spinal cord (1 patient);
[Peripheral nervous system];
Areflexia;
Peripheral neuropathy, progressive;
Delayed motor nerve conduction velocities
IMMUNOLOGY:
Immune deficiency;
Increased susceptibility to infections
LABORATORY ABNORMALITIES:
Reduced serum uric acid;
Undetectable urinary hypoxanthine;
Decreased PRPP synthetase activity in erythrocytes and fibroblasts
MISCELLANEOUS:
Early death due to infection;
Female carriers may show some manifestations, such as hearing impairment
MOLECULAR BASIS:
Caused by mutation in the phosphoribosylpyrophosphate synthetase 1
gene (PRPS1, 311850.0011)
*FIELD* CN
Cassandra L. Kniffin - revised: 4/9/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 04/25/2012
ckniffin: 4/9/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 4/9/2012
Cassandra L. Kniffin - updated: 5/4/2010
Victor A. McKusick - updated: 8/16/2007
Victor A. McKusick - updated: 4/25/1998
*FIELD* CD
Victor A. McKusick: 1/8/1991
*FIELD* ED
alopez: 04/20/2012
alopez: 4/12/2012
terry: 4/10/2012
ckniffin: 4/9/2012
carol: 10/27/2011
carol: 10/26/2011
ckniffin: 10/25/2011
wwang: 5/4/2010
ckniffin: 4/16/2008
alopez: 8/22/2007
terry: 8/16/2007
mgross: 3/17/2004
ckniffin: 8/28/2002
carol: 5/2/1998
terry: 4/25/1998
mimadm: 2/27/1994
carol: 6/28/1993
carol: 2/28/1991
carol: 2/4/1991
carol: 2/1/1991
carol: 1/8/1991
*RECORD*
*FIELD* NO
301835
*FIELD* TI
#301835 ARTS SYNDROME; ARTS
;;MENTAL RETARDATION, X-LINKED, SYNDROMIC, ARTS TYPE; MRXSARTS;;
read moreATAXIA, FATAL X-LINKED, WITH DEAFNESS AND LOSS OF VISION;;
MENTAL RETARDATION, X-LINKED, SYNDROMIC 18; MRXS18
*FIELD* TX
A number sign (#) is used with this entry because of evidence that Arts
syndrome is caused by loss-of-function mutations in the PRPS1 gene
(311850).
X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) is an
allelic disorder resulting from decreased enzyme activity. Affected
individuals have neurologic symptoms, including sensorineural deafness.
Another allelic disorder, PRPS-related gout (300661), results from
increased enzyme activity. Some affected patients have neurologic
symptoms, including sensorineural deafness.
DESCRIPTION
Arts syndrome is an X-linked disorder characterized by mental
retardation, early-onset hypotonia, ataxia, delayed motor development,
hearing impairment, and optic atrophy (de Brouwer et al., 2007).
Susceptibility to infections, especially of the upper respiratory tract,
can result in early death.
CLINICAL FEATURES
In 12 boys in 3 generations of a kindred in an X-linked recessive
pattern of inheritance, Arts et al. (1993) described a disorder leading
to death in early childhood. The manifestations were early-onset
floppiness, ataxia, liability to infections, especially of the upper
respiratory tract, deafness, and later, a flaccid tetraplegia and
areflexia. Although 1 boy was still alive at the age of 12 years, 11 had
died before the age of 5 years. The surviving boy required ventilation
at night and was nearly blind due to optic atrophy. In the only patient
in whom the central nervous system (CNS) could be examined at autopsy,
almost complete absence of myelin in the posterior columns of the spinal
cord was found. Among the female carriers, hearing impairment in early
adulthood appeared to be a feature.
Kremer et al. (1996) noted that infections were the cause of death
before the age of 6 years in 11 of the 12 boys reported by Arts et al.
(1993). The oldest patient, then 16 years of age, had become nearly
blind owing to optic atrophy and lived in an institution for the
visually and mentally handicapped. Clinical signs indicated impairment
of the posterior columns, peripheral motor and sensory neurons, and the
second and eighth cranial nerves and/or nuclei. In addition to
perceptive hearing loss, ataxic diplegia, extensor plantar reflexes,
hypotonia, and hyper- or hyporeflexia were thought to be features of the
heterozygous state. Kremer et al. (1996) noted the phenotypic
similarities to the family reported by Schmidley et al. (1987) (301790).
Moran et al. (2012) reported a young boy with a complex phenotype
comprising Arts syndrome and PRPS1 superactivity. He had developmental
delay, hypotonia, areflexia, motor neuropathy, sensorineural hearing
loss, and a Chiari I malformation. Laboratory studies showed increased
serum uric acid and increased urinary hypoxanthine consistent with PRPS1
superactivity, but he did not have gout. In addition, he had recurrent
infections and early death at age 27 months from infection, consistent
with Arts syndrome. A maternal uncle with similar symptoms had died of
pneumonia at age 2.
MAPPING
Using linkage analysis, Kremer et al. (1996) localized the gene (or
genes) responsible for the Arts syndrome phenotype to Xq21.33-q24
between DXS1231 and DXS1001 with a maximum lod score of 6.97. They noted
that the gene encoding proteolipid protein (300401), which codes for 2
myelin proteins of the central nervous system, is located in this region
and should be considered as a candidate gene for the disorder. However,
no mutations were found in the protein-coding part of the gene.
By linkage analysis in a Dutch family and an Australian family, de
Brouwer et al. (2007) mapped the candidate gene to Xq22.1-q24.
MOLECULAR GENETICS
Using oligonucleotide microarray expression profiling in fibroblasts
from 2 probands of a Dutch family with Arts syndrome, de Brouwer et al.
(2007) found reduced expression levels of the PRPS1 gene (311850).
Sequencing of PRPS1 led to the identification of 2 different missense
mutations, L152P (311850.0011) in the Dutch family and Q133P
(311850.0012) in the Australian family. Both mutations resulted in a
loss of PRPS1 activity, as was shown in silico by molecular modeling and
in vitro by enzyme assays in erythrocytes and fibroblasts from patients.
Gain-of-function mutations in PRPS1 result in PRPS-related gout (see
300661). The loss-of-function mutations of PRPS1 likely result in
impaired purine biosynthesis, which was supported by the undetectable
hypoxanthine in urine and the reduced uric acid levels in serum from
patients. De Brouwer et al. (2007) suggested that treatment with
S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy
to replenish low levels of purines. A clinical trial involving the 2
affected Australian brothers was underway. De Brouwer et al. (2010)
reported preliminary results of the 2 Australian brothers with Arts
syndrome, which revealed some improvement of their condition.
In a patient with a complex phenotype comprising Arts syndrome and PRPS1
superactivity, Moran et al. (2012) detected a missense mutation in the
transversion in exon 4 of the PRPS1 gene (V142L; 311850.0017). Both the
mother and grandmother were heterozygous for the mutation. Molecular
modeling predicted that the substitution would disrupt allosteric sites
involved in inhibition of PRPS1, resulting in a gain of enzyme function,
and the ATP-binding site, resulting in a loss of enzyme function.
Patient fibroblasts showed normal PRPP synthetase activity, whereas
erythrocytes showed a loss of enzyme activity, suggesting that the
effect of the V142L mutation on protein activity depends on cell type.
Moran et al. (2012) postulated a gain-of-function effect in
proliferating cells and a loss-of-function effect in postmitotic cells.
The report indicated that PRPS1 missense mutations can cause a
continuous spectrum of features ranging from progressive nonsyndromic
postlingual hearing impairment to uric acid overproduction, neuropathy,
and recurrent infections depending on the functional sites affected.
*FIELD* RF
1. Arts, W. F. M.; Loonen, M. C. B.; Sengers, R. C. A.; Slooff, J.
L.: X-linked ataxia, weakness, deafness, and loss of vision in early
childhood with a fatal course. Ann. Neurol. 33: 535-539, 1993.
2. de Brouwer, A. P. M.; van Bokhoven, H.; Nabuurs, S. B.; Arts, W.
F.; Christodoulou, J.; Duley, J.: PRPS1 mutations: four distinct
syndromes and potential treatment. Am. J. Hum. Genet. 86: 506-518,
2010.
3. de Brouwer, A. P. M.; Williams, K. L.; Duley, J. A.; van Kuilenburg,
A. B. P.; Nabuurs, S. B.; Egmont-Petersen, M.; Lugtenberg, D.; Zoetekouw,
L.; Banning, M. J. G.; Roeffen, M.; Hamel, B. C. J.; Weaving, L.;
Ouvrier, R. A.; Donald, J. A.; Wevers, R. A.; Christodoulou, J.; van
Bokhoven, H.: Arts syndrome is caused by loss-of-function mutations
in PRPS1. Am. J. Hum. Genet. 81: 507-518, 2007.
4. Kremer, H.; Hamel, B. C. J.; van den Helm, B.; Arts, W. F. M.;
de Wijs, I. J.; Sistermans, E. A.; Ropers, H.-H.; Mariman, E. C. M.
: Localization of the gene (or genes) for a syndrome with X-linked
mental retardation, ataxia, weakness, hearing impairment, loss of
vision and a fatal course in early childhood. Hum. Genet. 98: 513-517,
1996.
5. Moran, R.; Kuilenburg, A. B. P.; Duley, J.; Nabuurs, S. B.; Retno-Fitri,
A.; Christodoulou, J.; Roelofsen, J.; Yntema, H. G.; Friedman, N.
R.; van Bokhoven, H.; de Brouwer, A. P. M.: Phosphoribosylpyrophosphate
synthetase superactivity and recurrent infections is caused by a p.val142-to-leu
mutation in PRS-I. Am. J. Med. Genet. 158A: 455-460, 2012.
6. Schmidley, J. W.; Levinsohn, M. W.; Manetto, V.: Infantile X-linked
ataxia and deafness: a new clinicopathologic entity. Neurology 37:
1344-1349, 1987.
*FIELD* CS
INHERITANCE:
X-linked recessive
GROWTH:
[Other];
Poor growth
HEAD AND NECK:
[Ears];
Hearing impairment, sensorineural;
[Eyes];
Optic atrophy;
Loss of vision;
Nystagmus;
[Mouth];
Drooling
RESPIRATORY:
Recurrent respiratory tract infections
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Hypotonia, neonatal;
Muscle weakness, progressive
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Lack of speech;
Ataxia;
Seizures;
Flaccid tetraplegia;
Hyperreflexia (less common);
Absence of myelin in the posterior column of the spinal cord (1 patient);
[Peripheral nervous system];
Areflexia;
Peripheral neuropathy, progressive;
Delayed motor nerve conduction velocities
IMMUNOLOGY:
Immune deficiency;
Increased susceptibility to infections
LABORATORY ABNORMALITIES:
Reduced serum uric acid;
Undetectable urinary hypoxanthine;
Decreased PRPP synthetase activity in erythrocytes and fibroblasts
MISCELLANEOUS:
Early death due to infection;
Female carriers may show some manifestations, such as hearing impairment
MOLECULAR BASIS:
Caused by mutation in the phosphoribosylpyrophosphate synthetase 1
gene (PRPS1, 311850.0011)
*FIELD* CN
Cassandra L. Kniffin - revised: 4/9/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 04/25/2012
ckniffin: 4/9/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 4/9/2012
Cassandra L. Kniffin - updated: 5/4/2010
Victor A. McKusick - updated: 8/16/2007
Victor A. McKusick - updated: 4/25/1998
*FIELD* CD
Victor A. McKusick: 1/8/1991
*FIELD* ED
alopez: 04/20/2012
alopez: 4/12/2012
terry: 4/10/2012
ckniffin: 4/9/2012
carol: 10/27/2011
carol: 10/26/2011
ckniffin: 10/25/2011
wwang: 5/4/2010
ckniffin: 4/16/2008
alopez: 8/22/2007
terry: 8/16/2007
mgross: 3/17/2004
ckniffin: 8/28/2002
carol: 5/2/1998
terry: 4/25/1998
mimadm: 2/27/1994
carol: 6/28/1993
carol: 2/28/1991
carol: 2/4/1991
carol: 2/1/1991
carol: 1/8/1991
MIM
304500
*RECORD*
*FIELD* NO
304500
*FIELD* TI
#304500 DEAFNESS, X-LINKED 1; DFNX1
;;DEAFNESS, X-LINKED 2, SENSORINEURAL CONGENITAL; DFN2
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
X-linked deafness-1 is caused by mutation in the PRPS1 gene (311850).
NOMENCLATURE
Petersen et al. (2008) proposed the designation DFNX1 for this locus.
CLINICAL FEATURES
Tyson et al. (1996) reevaluated a 4-generation British American family
with congenital profound sensorineural hearing loss in males, similar to
that ascribed to the previously unmapped locus DFN2. In this family,
female carriers had a mild/moderate hearing loss affecting the high
frequencies.
Liu et al. (2010) studied 14 affected and 29 unaffected members of a
large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss. Age at onset of hearing impairment was between 5 and 15
years for males and in the fifth decade for females. Affected males
exhibited symmetric, progressive, severe-to-profound hearing loss with
flat-shaped audio profiles at 24 years to 50 years of age. Obligate
female carriers had either symmetric or asymmetric hearing loss that
varied from mild to moderate in degree.
MAPPING
By linkage analysis using polymorphic microsatellite markers in a
4-generation British American family with congenital sensorineural
hearing loss, Tyson et al. (1996) found that the DFN2 locus maps to
Xq22. A maximum 2-point lod score of 2.91 at theta = 0.0 was observed
with a fully informative dinucleotide repeat at COL4A5 (303630), which
had previously been mapped to Xq22, and flanking recombinations were
observed at DXS990 and DXS1001.
In a large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss, Liu et al. (2010) performed linkage analysis and obtained
a maximum 2-point lod score of 4.25 with marker DXS8096 (theta = 0).
Recombination events defined a 5.4-cM critical interval between DXS8020
and DXS8055, overlapping the DFN2 locus.
MOLECULAR GENETICS
In a large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss mapping to the DNF2 locus, Liu et al. (2010) analyzed 14
candidate genes and identified a missense mutation in the PRPS1 gene
(D65N; 311850.0013) that cosegregated with the phenotype. Analysis of
the PRPS1 gene in the British American DFN2 family previously reported
by Tyson et al. (1996) revealed a different missense mutation (A87T;
311850.0014); missense mutations were also detected in DFN2 families
previously reported by Manolis et al. (1999) and Cui et al. (2004)
(311850.0015 and 311850.0016, respectively).
HISTORY
There are many early reports of an X-linked form of congenital deafness
(e.g., Dow and Poynter, 1930; Mitsuda et al., 1952; Stevenson, cited by
Deraemaeker, 1958; Deraemaeker, 1958; Sataloff et al., 1955; Parker,
1958; Fraser, 1965). In the family reported by Dow and Poynter (1930), 4
affected males married deaf-mute women who probably had the autosomal
recessive form of the disease because no children were affected. The
deafness is of the sensorineural type.
William Wilde (1815-1876), the father of Oscar Wilde and a distinguished
ear, nose, and throat surgeon, conducted a large survey of deafness in
Ireland in 1851 (Wilde, 1853). In his report he noted that 'the
proportion of male deaf mutes exceeds the female considerably but it
differs somewhat in the 2 great classes of congenital and acquired
deafness.' In the Wilde data, the ratio of males to females was 100:75
for congenital deafness and 100:91 for acquired deafness. Reardon (1990)
reanalyzed the data from the Wilde survey and suggested that 5% of
congenital male deafness was the result of X-linked inheritance. The
result correlated well with the estimate of Fraser (1965) that X-linked
inheritance accounts for 6.2% of male genetic deafness.
Many families with congenital sensorineural deafness are found to have
the gusher-deafness syndrome (304400) with typical radiologic changes in
the temporal bone (Reardon et al., 1991). Some congenital sensorineural
deafness may represent the entity that Lalwani et al. (1994) found to be
linked to Xp21.2; see 300030.
For a review of the genetic causes of nonsyndromic sensorineural hearing
loss, see Willems (2000).
*FIELD* SA
McRae et al. (1969); Richards (1963)
*FIELD* RF
1. Cui, B.; Zhang, H.; Lu, Y.; Zhong, W.; Pei, G.; Kong, X.; Hu, L.
: Refinement of the locus for non-syndromic sensorineural deafness
(DFN2) J. Genet. 83: 35-38, 2004.
2. Deraemaeker, R.: Sex-linked congenital deafness. Acta Genet.
Statist. Med. 8: 228-231, 1958.
3. Dow, G. S.; Poynter, C. I.: The Dar family. Eugen. News 15:
128-130, 1930.
4. Fraser, G. R.: Sex-linked recessive congenital deafness and the
excess of males in profound childhood deafness. Ann. Hum. Genet. 29:
171-196, 1965.
5. Lalwani, A. K.; Brister, J. R.; Fex, J.; Grundfast, K. M.; Pikus,
A. T.; Ploplis, B.; San/Agustin, T.; Skarka, H.; Wilcox, E. R.: A
new nonsyndromic X-linked sensorineural hearing impairment linked
to Xp21.2. Am. J. Hum. Genet. 55: 685-694, 1994.
6. Liu, X.; Han, D.; Li, J.; Han, B.; Ouyang, X.; Cheng, J.; Li, X.;
Jin, Z.; Wang, Y.; Bitner-Glindzicz, M.; Kong, X.; Xu, H.; and 10
others: Loss-of-function mutations in the PRPS1 gene cause a type
of nonsyndromic X-linked sensorineural deafness, DFN2. Am. J. Hum.
Genet. 86: 65-71, 2010.
7. Manolis, E. N.; Eavey, R. D.; Sangwatanaroj, S.; Halpin, C.; Rosenbaum,
S.; Watkins, H.; Jarcho, J.; Seidman, C. E.; Seidman, J. G.: Hereditary
postlingual sensorineural hearing loss mapping to chromosome Xq21. Am.
J. Otol. 20: 621-626, 1999.
8. McRae, K. N.; Uchida, I. A.; Lewis, M.; Denniston, C.: Sex-linked
congenital deafness. Am. J. Hum. Genet. 21: 415-422, 1969.
9. Mitsuda, H.; Inoue, S.; Kazama, Y.: Eine Familie mit rezessiv
geschlechtsgebundener Taubstummheit. Jpn. J. Hum. Genet. 27: 142
only, 1952.
10. Parker, N.: Congenital deafness due to a sex-linked recessive
gene. Am. J. Hum. Genet. 10: 196-200, 1958.
11. Petersen, M. B.; Wang, Q.; Willems, P. J.: Sex-linked deafness. Clin.
Genet. 73: 14-23, 2008.
12. Reardon, W.: Sex linked deafness: Wilde revisited. J. Med. Genet. 27:
376-379, 1990.
13. Reardon, W.; Middleton-Price, H. R.; Sandkuijl, L.; Phelps, P.;
Bellman, S.; Luxon, L.; Pembrey, M. E.; Malcolm, S.: A multipedigree
linkage study of X-linked deafness: linkage to Xq13-q21 and evidence
for genetic heterogeneity. Genomics 11: 885-894, 1991.
14. Richards, B. W.: Sex-linked deaf-mutism. Ann. Hum. Genet. 26:
195-199, 1963.
15. Sataloff, J.; Pastore, P. N.; Bloom, E.: Sex-linked hereditary
deafness. Am. J. Hum. Genet. 7: 201-203, 1955.
16. Tyson, J.; Bellman, S.; Newton, V.; Simpson, P.; Malcolm, S.;
Pembrey, M. E.; Bitner-Glindzicz, M.: Mapping of DFN2 to Xq22. Hum.
Molec. Genet. 5: 2055-2060, 1996.
17. Wilde, W. R.: Practical Observations on Aural Surgery and the
Nature and Diagnosis of Diseases of the Ear. London: Churchill (pub.)
1853.
18. Willems, P. J.: Genetic causes of hearing loss. New Eng. J.
Med. 342: 1101-1109, 2000.
*FIELD* CS
Ears:
Congenital hearing loss;
Perceptive hearing loss
Inheritance:
X-linked
*FIELD* ED
joanna: 02/07/2011
*FIELD* CN
Marla J. F. O'Neill - updated: 2/26/2010
Cassandra L. Kniffin - updated: 3/17/2008
Victor A. McKusick - updated: 5/25/2000
Victor A. McKusick - updated: 11/13/1997
Victor A. McKusick - updated: 3/6/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 04/02/2010
carol: 2/26/2010
wwang: 3/18/2008
ckniffin: 3/17/2008
carol: 3/18/2004
carol: 5/8/2002
carol: 8/24/2001
carol: 5/25/2000
mark: 11/13/1997
terry: 11/12/1997
jenny: 3/6/1997
terry: 2/13/1997
mark: 10/23/1996
mark: 10/18/1996
terry: 1/31/1995
pfoster: 7/19/1994
supermim: 3/17/1992
carol: 7/5/1990
supermim: 3/20/1990
*RECORD*
*FIELD* NO
304500
*FIELD* TI
#304500 DEAFNESS, X-LINKED 1; DFNX1
;;DEAFNESS, X-LINKED 2, SENSORINEURAL CONGENITAL; DFN2
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
X-linked deafness-1 is caused by mutation in the PRPS1 gene (311850).
NOMENCLATURE
Petersen et al. (2008) proposed the designation DFNX1 for this locus.
CLINICAL FEATURES
Tyson et al. (1996) reevaluated a 4-generation British American family
with congenital profound sensorineural hearing loss in males, similar to
that ascribed to the previously unmapped locus DFN2. In this family,
female carriers had a mild/moderate hearing loss affecting the high
frequencies.
Liu et al. (2010) studied 14 affected and 29 unaffected members of a
large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss. Age at onset of hearing impairment was between 5 and 15
years for males and in the fifth decade for females. Affected males
exhibited symmetric, progressive, severe-to-profound hearing loss with
flat-shaped audio profiles at 24 years to 50 years of age. Obligate
female carriers had either symmetric or asymmetric hearing loss that
varied from mild to moderate in degree.
MAPPING
By linkage analysis using polymorphic microsatellite markers in a
4-generation British American family with congenital sensorineural
hearing loss, Tyson et al. (1996) found that the DFN2 locus maps to
Xq22. A maximum 2-point lod score of 2.91 at theta = 0.0 was observed
with a fully informative dinucleotide repeat at COL4A5 (303630), which
had previously been mapped to Xq22, and flanking recombinations were
observed at DXS990 and DXS1001.
In a large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss, Liu et al. (2010) performed linkage analysis and obtained
a maximum 2-point lod score of 4.25 with marker DXS8096 (theta = 0).
Recombination events defined a 5.4-cM critical interval between DXS8020
and DXS8055, overlapping the DFN2 locus.
MOLECULAR GENETICS
In a large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss mapping to the DNF2 locus, Liu et al. (2010) analyzed 14
candidate genes and identified a missense mutation in the PRPS1 gene
(D65N; 311850.0013) that cosegregated with the phenotype. Analysis of
the PRPS1 gene in the British American DFN2 family previously reported
by Tyson et al. (1996) revealed a different missense mutation (A87T;
311850.0014); missense mutations were also detected in DFN2 families
previously reported by Manolis et al. (1999) and Cui et al. (2004)
(311850.0015 and 311850.0016, respectively).
HISTORY
There are many early reports of an X-linked form of congenital deafness
(e.g., Dow and Poynter, 1930; Mitsuda et al., 1952; Stevenson, cited by
Deraemaeker, 1958; Deraemaeker, 1958; Sataloff et al., 1955; Parker,
1958; Fraser, 1965). In the family reported by Dow and Poynter (1930), 4
affected males married deaf-mute women who probably had the autosomal
recessive form of the disease because no children were affected. The
deafness is of the sensorineural type.
William Wilde (1815-1876), the father of Oscar Wilde and a distinguished
ear, nose, and throat surgeon, conducted a large survey of deafness in
Ireland in 1851 (Wilde, 1853). In his report he noted that 'the
proportion of male deaf mutes exceeds the female considerably but it
differs somewhat in the 2 great classes of congenital and acquired
deafness.' In the Wilde data, the ratio of males to females was 100:75
for congenital deafness and 100:91 for acquired deafness. Reardon (1990)
reanalyzed the data from the Wilde survey and suggested that 5% of
congenital male deafness was the result of X-linked inheritance. The
result correlated well with the estimate of Fraser (1965) that X-linked
inheritance accounts for 6.2% of male genetic deafness.
Many families with congenital sensorineural deafness are found to have
the gusher-deafness syndrome (304400) with typical radiologic changes in
the temporal bone (Reardon et al., 1991). Some congenital sensorineural
deafness may represent the entity that Lalwani et al. (1994) found to be
linked to Xp21.2; see 300030.
For a review of the genetic causes of nonsyndromic sensorineural hearing
loss, see Willems (2000).
*FIELD* SA
McRae et al. (1969); Richards (1963)
*FIELD* RF
1. Cui, B.; Zhang, H.; Lu, Y.; Zhong, W.; Pei, G.; Kong, X.; Hu, L.
: Refinement of the locus for non-syndromic sensorineural deafness
(DFN2) J. Genet. 83: 35-38, 2004.
2. Deraemaeker, R.: Sex-linked congenital deafness. Acta Genet.
Statist. Med. 8: 228-231, 1958.
3. Dow, G. S.; Poynter, C. I.: The Dar family. Eugen. News 15:
128-130, 1930.
4. Fraser, G. R.: Sex-linked recessive congenital deafness and the
excess of males in profound childhood deafness. Ann. Hum. Genet. 29:
171-196, 1965.
5. Lalwani, A. K.; Brister, J. R.; Fex, J.; Grundfast, K. M.; Pikus,
A. T.; Ploplis, B.; San/Agustin, T.; Skarka, H.; Wilcox, E. R.: A
new nonsyndromic X-linked sensorineural hearing impairment linked
to Xp21.2. Am. J. Hum. Genet. 55: 685-694, 1994.
6. Liu, X.; Han, D.; Li, J.; Han, B.; Ouyang, X.; Cheng, J.; Li, X.;
Jin, Z.; Wang, Y.; Bitner-Glindzicz, M.; Kong, X.; Xu, H.; and 10
others: Loss-of-function mutations in the PRPS1 gene cause a type
of nonsyndromic X-linked sensorineural deafness, DFN2. Am. J. Hum.
Genet. 86: 65-71, 2010.
7. Manolis, E. N.; Eavey, R. D.; Sangwatanaroj, S.; Halpin, C.; Rosenbaum,
S.; Watkins, H.; Jarcho, J.; Seidman, C. E.; Seidman, J. G.: Hereditary
postlingual sensorineural hearing loss mapping to chromosome Xq21. Am.
J. Otol. 20: 621-626, 1999.
8. McRae, K. N.; Uchida, I. A.; Lewis, M.; Denniston, C.: Sex-linked
congenital deafness. Am. J. Hum. Genet. 21: 415-422, 1969.
9. Mitsuda, H.; Inoue, S.; Kazama, Y.: Eine Familie mit rezessiv
geschlechtsgebundener Taubstummheit. Jpn. J. Hum. Genet. 27: 142
only, 1952.
10. Parker, N.: Congenital deafness due to a sex-linked recessive
gene. Am. J. Hum. Genet. 10: 196-200, 1958.
11. Petersen, M. B.; Wang, Q.; Willems, P. J.: Sex-linked deafness. Clin.
Genet. 73: 14-23, 2008.
12. Reardon, W.: Sex linked deafness: Wilde revisited. J. Med. Genet. 27:
376-379, 1990.
13. Reardon, W.; Middleton-Price, H. R.; Sandkuijl, L.; Phelps, P.;
Bellman, S.; Luxon, L.; Pembrey, M. E.; Malcolm, S.: A multipedigree
linkage study of X-linked deafness: linkage to Xq13-q21 and evidence
for genetic heterogeneity. Genomics 11: 885-894, 1991.
14. Richards, B. W.: Sex-linked deaf-mutism. Ann. Hum. Genet. 26:
195-199, 1963.
15. Sataloff, J.; Pastore, P. N.; Bloom, E.: Sex-linked hereditary
deafness. Am. J. Hum. Genet. 7: 201-203, 1955.
16. Tyson, J.; Bellman, S.; Newton, V.; Simpson, P.; Malcolm, S.;
Pembrey, M. E.; Bitner-Glindzicz, M.: Mapping of DFN2 to Xq22. Hum.
Molec. Genet. 5: 2055-2060, 1996.
17. Wilde, W. R.: Practical Observations on Aural Surgery and the
Nature and Diagnosis of Diseases of the Ear. London: Churchill (pub.)
1853.
18. Willems, P. J.: Genetic causes of hearing loss. New Eng. J.
Med. 342: 1101-1109, 2000.
*FIELD* CS
Ears:
Congenital hearing loss;
Perceptive hearing loss
Inheritance:
X-linked
*FIELD* ED
joanna: 02/07/2011
*FIELD* CN
Marla J. F. O'Neill - updated: 2/26/2010
Cassandra L. Kniffin - updated: 3/17/2008
Victor A. McKusick - updated: 5/25/2000
Victor A. McKusick - updated: 11/13/1997
Victor A. McKusick - updated: 3/6/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
terry: 04/02/2010
carol: 2/26/2010
wwang: 3/18/2008
ckniffin: 3/17/2008
carol: 3/18/2004
carol: 5/8/2002
carol: 8/24/2001
carol: 5/25/2000
mark: 11/13/1997
terry: 11/12/1997
jenny: 3/6/1997
terry: 2/13/1997
mark: 10/23/1996
mark: 10/18/1996
terry: 1/31/1995
pfoster: 7/19/1994
supermim: 3/17/1992
carol: 7/5/1990
supermim: 3/20/1990
MIM
311070
*RECORD*
*FIELD* NO
311070
*FIELD* TI
#311070 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 5; CMTX5
;;OPTIC ATROPHY, POLYNEUROPATHY, AND DEAFNESS;;
read moreROSENBERG-CHUTORIAN SYNDROME;;
CHARCOT-MARIE-TOOTH NEUROPATHY, X-LINKED RECESSIVE, 5
*FIELD* TX
A number sign (#) is used with this entry because X-linked recessive
Charcot-Marie-Tooth disease-5 (CMTX5) is caused by mutation in the gene
encoding phosphoribosylpyrophosphate synthetase I (PRPS1; 311850).
PRPS1 superactivity (300661) is an allelic disorder resulting from
increased enzyme activity. Some affected patients have neurologic
symptoms, including sensorineural deafness. Another allelic disorder,
Arts syndrome (301835), results from loss of PRPS1 activity and has a
severe neurologic phenotype including mental retardation, early-onset
hypotonia, and susceptibility to infections.
DESCRIPTION
The phenotype of X-linked Charcot-Marie-Tooth disease-5 comprises the
triad of optic atrophy, deafness, and polyneuropathy. See 165199 and
258650 for possible autosomal dominant and autosomal recessive forms of
the disorder.
For a discussion of genetic heterogeneity of X-linked
Charcot-Marie-Tooth disease, see CMTX1 (302800).
CLINICAL FEATURES
Rosenberg and Chutorian (1967) reported 2 brothers with early-onset
hearing loss, lower leg weakness and atrophy beginning in childhood, and
progressive loss of vision beginning with optic atrophy at about age 20
years. The older brother had pes cavus, and both brothers required a
cane for walking by age 15 years. As adults, both had severe distal
weakness and atrophy in all extremities, with broad-based gait and
atrophy of the intrinsic hand muscles. Deep tendon reflexes were absent
in the legs, there was marked reduction of all sensory modalities below
the elbows and knees. Nerve conduction was moderately reduced. Intellect
was not affected. A 3.5-year-old nephew showed the same triad of
features. Later evidence suggested that the mother, grandmother, and
great-grandmother of the affected nephew may also have had slowly
progressive hearing loss, suggesting X-linked semidominant inheritance
(Pauli, 1984).
Pauli (1984) reported a family (family 'A') in which 3 males had
infantile or congenital onset of bilateral sensorineural hearing loss
and childhood-onset of peripheral neuropathy. There was slow
progression, but the 2 older patients developed severe motor disability
by ages 27 and 35 years. Two also had visual loss, 1 with optic atrophy.
Five female family members had hearing loss.
Kim et al. (2005) reported a Korean family in which 6 males were
affected with early-onset hearing loss, decreased visual acuity, and
motor impairment in an X-linked recessive pattern of inheritance.
Bilateral profound sensorineural hearing loss was present at an early
age. The patients had onset of progressive weakness of the lower
extremities and gait disturbances from ages 10 to 12 years. All
developed bilateral progressive visual failure starting at 8 to 13
years. The proband had bilateral optic disc pallor and decreased visual
evoked potentials, indicating optic nerve dysfunction. Obligate female
carriers were unaffected. Kim et al. (2005) noted that the phenotype
resembled that reported by Rosenberg and Chutorian (1967).
MAPPING
By X chromosome-wide linkage analysis of a Korean family, Kim et al.
(2005) identified a 15.2-cM candidate disease locus, termed CMTX5, on
chromosome Xq21.32-q24 between markers DXS990 and DXS8067 (maximum lod
score of 3.62 at DXS8077). The locus did not overlap with CMTX1, CMTX2
(302801), CMTX3 (302802), or Cowchock syndrome (CMTX4; 310490).
MOLECULAR GENETICS
In affected members of the families reported by Rosenberg and Chutorian
(1967) and Kim et al. (2005), Kim et al. (2007) identified 2 different
mutations in the PRPS1 gene (311850.0009 and 311850.0010, respectively).
The mutations were shown to result in decreased enzyme activity; none of
the affected individuals had increased uric acid or gout. Kim et al.
(2007) noted that both PRPS1 superactivity and CMT5X phenotypes share
neurologic features.
*FIELD* RF
1. Kim, H.-J.; Hong, S. H.; Ki, C.-S.; Kim, B.-J.; Shim, J.-S.; Cho,
S.-H.; Park, J.-H.; Kim, J.-W.: A novel locus for X-linked recessive
CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology 64:
1964-1967, 2005.
2. Kim, H.-J.; Sohn, K.-M.; Shy, M. E.; Krajewski, K. M.; Hwang, M.;
Park, J.-H.; Jang, S.-Y.; Won, H.-H.; Choi, B.-O.; Hong, S. H.; Kim,
B.-J.; Suh, Y.-L.; Ki, C.-S.; Lee, S.-Y.; Kim, S.-H.; Kim, J.-W.:
Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate
synthetase enzyme critical for nucleotide biosynthesis, cause hereditary
peripheral neuropathy with hearing loss and optic neuropathy (CMT5X). Am.
J. Hum. Genet. 81: 552-558, 2007.
3. Pauli, R. M.: Sensorineural deafness and peripheral neuropathy.
(Letter) Clin. Genet. 26: 383-384, 1984.
4. Rosenberg, R. N.; Chutorian, A.: Familial opticoacoustic nerve
degeneration and polyneuropathy. Neurology 17: 827-832, 1967.
*FIELD* CS
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Ears];
Hearing loss, senorineural, prelingual;
[Eyes];
Vision impairment, progressive (onset in late childhood, teens);
Optic nerve atrophy
SKELETAL:
[Feet];
Pes cavus
NEUROLOGIC:
[Peripheral nervous system];
Delayed motor development;
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Impaired gait, some patients are never able to run;
Areflexia of the lower limbs;
Distal sensory impairment;
Nerve conduction velocities (NCV) may be normal or mildly decreased
Sural nerve biopsy shows loss of both large and small myelinated fibers;
Increased endoneurial collagen;
Segmental demyelination/remyelination;
Onion bulb formations
MISCELLANEOUS:
Female carriers may have hearing loss;
Onset of motor disturbances in childhood;
Possible autosomal dominant (165199) and autosomal recessive (258650)
forms
MOLECULAR BASIS:
Caused by mutation in the phosphoribosylpyrophosphate synthetase 1
gene (PRPS1, 311850.0009)
*FIELD* CN
Cassandra L. Kniffin - updated: 8/16/2007
Cassandra L. Kniffin - revised: 12/21/2005
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/29/2011
joanna: 6/5/2009
ckniffin: 8/16/2007
joanna: 12/30/2005
ckniffin: 12/21/2005
*FIELD* CN
Cassandra L. Kniffin - updated: 8/16/2007
Cassandra L. Kniffin - updated: 12/21/2005
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
joanna: 08/23/2007
alopez: 8/22/2007
carol: 8/17/2007
ckniffin: 8/16/2007
carol: 12/23/2005
ckniffin: 12/21/2005
mimadm: 2/28/1994
supermim: 3/17/1992
carol: 3/2/1992
supermim: 3/20/1990
ddp: 10/26/1989
*RECORD*
*FIELD* NO
311070
*FIELD* TI
#311070 CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 5; CMTX5
;;OPTIC ATROPHY, POLYNEUROPATHY, AND DEAFNESS;;
read moreROSENBERG-CHUTORIAN SYNDROME;;
CHARCOT-MARIE-TOOTH NEUROPATHY, X-LINKED RECESSIVE, 5
*FIELD* TX
A number sign (#) is used with this entry because X-linked recessive
Charcot-Marie-Tooth disease-5 (CMTX5) is caused by mutation in the gene
encoding phosphoribosylpyrophosphate synthetase I (PRPS1; 311850).
PRPS1 superactivity (300661) is an allelic disorder resulting from
increased enzyme activity. Some affected patients have neurologic
symptoms, including sensorineural deafness. Another allelic disorder,
Arts syndrome (301835), results from loss of PRPS1 activity and has a
severe neurologic phenotype including mental retardation, early-onset
hypotonia, and susceptibility to infections.
DESCRIPTION
The phenotype of X-linked Charcot-Marie-Tooth disease-5 comprises the
triad of optic atrophy, deafness, and polyneuropathy. See 165199 and
258650 for possible autosomal dominant and autosomal recessive forms of
the disorder.
For a discussion of genetic heterogeneity of X-linked
Charcot-Marie-Tooth disease, see CMTX1 (302800).
CLINICAL FEATURES
Rosenberg and Chutorian (1967) reported 2 brothers with early-onset
hearing loss, lower leg weakness and atrophy beginning in childhood, and
progressive loss of vision beginning with optic atrophy at about age 20
years. The older brother had pes cavus, and both brothers required a
cane for walking by age 15 years. As adults, both had severe distal
weakness and atrophy in all extremities, with broad-based gait and
atrophy of the intrinsic hand muscles. Deep tendon reflexes were absent
in the legs, there was marked reduction of all sensory modalities below
the elbows and knees. Nerve conduction was moderately reduced. Intellect
was not affected. A 3.5-year-old nephew showed the same triad of
features. Later evidence suggested that the mother, grandmother, and
great-grandmother of the affected nephew may also have had slowly
progressive hearing loss, suggesting X-linked semidominant inheritance
(Pauli, 1984).
Pauli (1984) reported a family (family 'A') in which 3 males had
infantile or congenital onset of bilateral sensorineural hearing loss
and childhood-onset of peripheral neuropathy. There was slow
progression, but the 2 older patients developed severe motor disability
by ages 27 and 35 years. Two also had visual loss, 1 with optic atrophy.
Five female family members had hearing loss.
Kim et al. (2005) reported a Korean family in which 6 males were
affected with early-onset hearing loss, decreased visual acuity, and
motor impairment in an X-linked recessive pattern of inheritance.
Bilateral profound sensorineural hearing loss was present at an early
age. The patients had onset of progressive weakness of the lower
extremities and gait disturbances from ages 10 to 12 years. All
developed bilateral progressive visual failure starting at 8 to 13
years. The proband had bilateral optic disc pallor and decreased visual
evoked potentials, indicating optic nerve dysfunction. Obligate female
carriers were unaffected. Kim et al. (2005) noted that the phenotype
resembled that reported by Rosenberg and Chutorian (1967).
MAPPING
By X chromosome-wide linkage analysis of a Korean family, Kim et al.
(2005) identified a 15.2-cM candidate disease locus, termed CMTX5, on
chromosome Xq21.32-q24 between markers DXS990 and DXS8067 (maximum lod
score of 3.62 at DXS8077). The locus did not overlap with CMTX1, CMTX2
(302801), CMTX3 (302802), or Cowchock syndrome (CMTX4; 310490).
MOLECULAR GENETICS
In affected members of the families reported by Rosenberg and Chutorian
(1967) and Kim et al. (2005), Kim et al. (2007) identified 2 different
mutations in the PRPS1 gene (311850.0009 and 311850.0010, respectively).
The mutations were shown to result in decreased enzyme activity; none of
the affected individuals had increased uric acid or gout. Kim et al.
(2007) noted that both PRPS1 superactivity and CMT5X phenotypes share
neurologic features.
*FIELD* RF
1. Kim, H.-J.; Hong, S. H.; Ki, C.-S.; Kim, B.-J.; Shim, J.-S.; Cho,
S.-H.; Park, J.-H.; Kim, J.-W.: A novel locus for X-linked recessive
CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology 64:
1964-1967, 2005.
2. Kim, H.-J.; Sohn, K.-M.; Shy, M. E.; Krajewski, K. M.; Hwang, M.;
Park, J.-H.; Jang, S.-Y.; Won, H.-H.; Choi, B.-O.; Hong, S. H.; Kim,
B.-J.; Suh, Y.-L.; Ki, C.-S.; Lee, S.-Y.; Kim, S.-H.; Kim, J.-W.:
Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate
synthetase enzyme critical for nucleotide biosynthesis, cause hereditary
peripheral neuropathy with hearing loss and optic neuropathy (CMT5X). Am.
J. Hum. Genet. 81: 552-558, 2007.
3. Pauli, R. M.: Sensorineural deafness and peripheral neuropathy.
(Letter) Clin. Genet. 26: 383-384, 1984.
4. Rosenberg, R. N.; Chutorian, A.: Familial opticoacoustic nerve
degeneration and polyneuropathy. Neurology 17: 827-832, 1967.
*FIELD* CS
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Ears];
Hearing loss, senorineural, prelingual;
[Eyes];
Vision impairment, progressive (onset in late childhood, teens);
Optic nerve atrophy
SKELETAL:
[Feet];
Pes cavus
NEUROLOGIC:
[Peripheral nervous system];
Delayed motor development;
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Impaired gait, some patients are never able to run;
Areflexia of the lower limbs;
Distal sensory impairment;
Nerve conduction velocities (NCV) may be normal or mildly decreased
Sural nerve biopsy shows loss of both large and small myelinated fibers;
Increased endoneurial collagen;
Segmental demyelination/remyelination;
Onion bulb formations
MISCELLANEOUS:
Female carriers may have hearing loss;
Onset of motor disturbances in childhood;
Possible autosomal dominant (165199) and autosomal recessive (258650)
forms
MOLECULAR BASIS:
Caused by mutation in the phosphoribosylpyrophosphate synthetase 1
gene (PRPS1, 311850.0009)
*FIELD* CN
Cassandra L. Kniffin - updated: 8/16/2007
Cassandra L. Kniffin - revised: 12/21/2005
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/29/2011
joanna: 6/5/2009
ckniffin: 8/16/2007
joanna: 12/30/2005
ckniffin: 12/21/2005
*FIELD* CN
Cassandra L. Kniffin - updated: 8/16/2007
Cassandra L. Kniffin - updated: 12/21/2005
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
joanna: 08/23/2007
alopez: 8/22/2007
carol: 8/17/2007
ckniffin: 8/16/2007
carol: 12/23/2005
ckniffin: 12/21/2005
mimadm: 2/28/1994
supermim: 3/17/1992
carol: 3/2/1992
supermim: 3/20/1990
ddp: 10/26/1989
MIM
311850
*RECORD*
*FIELD* NO
311850
*FIELD* TI
*311850 PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1
*FIELD* TX
DESCRIPTION
Phosphoribosylpyrophosphate synthetase (PRPS; EC 2.7.6.1) catalyzes the
read morephosphoribosylation of ribose 5-phosphate to
5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and
salvage pathways of purine and pyrimidine biosynthesis (Roessler et al.,
1990). Three PRPS genes have been identified: the widely expressed PRPS1
and PRPS2 (311860) genes, which map to chromosome Xq22-q24 and Xp22,
respectively, and PRPS3 (PRPS1L1; 611566), which maps to chromosome 7
and appears to be transcribed only in testis (Becker, 2001).
CLONING
Roessler et al. (1990) isolated a partial clone corresponding to the
PRPS1 gene from a human lymphoblast cDNA library. The deduced PRPS1
protein has 318 amino acids and shares 95% amino acid homology with
PRPS2. Becker et al. (1990) also cloned the PRPS1 gene and detected a
2.3-kb mRNA transcript.
By Northern blot analysis using rat Prps1 as probe, Taira et al. (1989)
detected a 2.3-kb transcript in human adipose tissue, testis, and
placenta and in 2 human cell lines.
Kim et al. (2007) demonstrated that the PRPS1 amino acid sequence shows
an exceptionally high degree of conservation, with homologies greater
than 95% across different species from zebrafish to human.
GENE STRUCTURE
The PRPS1 gene spans over 30 kb and contains 7 exons (Becker, 2001).
MAPPING
By the Goss-Harris method, Becker et al. (1978) concluded that the order
of loci on chromosome Xq is G6PD (305900)--HPRT1
(308000)--PRPS1--alpha-GAL (GLA; 300644)--PGK1 (311800)--centromere.
Becker et al. (1979) assigned the PRPS1 locus to a position between the
GLA and HPRT1 loci, particularly close to the latter, and discussed the
functional significance of the proximity of the genes for their
biochemically related functions.
Becker et al. (1990) mapped PRPS1 to Xq22-q24 by a combination of in
situ hybridization and study of human/rodent somatic cell hybrids.
- Pseudogene
By in situ chromosomal hybridization, Becker et al. (1990) identified a
PRPS1-related gene or pseudogene (PRPS1L2) on chromosome 9q33-q34.
MOLECULAR GENETICS
De Brouwer et al. (2010) provided a review of the clinical and molecular
features of the 4 distinct syndromes caused by mutation in the PRPS1
gene: PRPS1 superactivity (300661), X-linked Charcot-Marie-Tooth
disease-5 (CMTX5; 311070), Arts syndrome (301835), and isolated X-linked
sensorineural deafness (304500). The neurologic phenotype in all 4
PRPS1-related disorders seems to result primarily from reduced levels of
GTP and possibly other purine nucleotides including ATP, suggesting that
these disorders belong to the same disease spectrum. Preliminary results
of S-adenosylmethionine (SAM) supplementation in 2 Australian brothers
with Arts syndrome revealed some improvement of their condition,
suggesting that SAM supplementation could potentially alleviate some of
the symptoms of patients with PRPS1 spectrum diseases by replenishing
purine nucleotides.
- Phosphoribosylpyrophosphate Synthetase Superactivity
In patients with phosphoribosylpyrophosphate synthetase superactivity
(300661), Roessler et al. (1991, 1993) and Becker et al. (1995)
identified mutations in the PRPS1 gene (311850.0001-311850.0008). All
patients except 1 had hyperuricemia, neurodevelopmental abnormalities,
and sensorineural deafness; the other patient had only hyperuricemia and
gout. Functional expression studies of all mutations showed that enzyme
overactivity was due to alteration of allosteric feedback mechanisms.
- Charcot-Marie-Tooth Disease, X-linked Recessive, 5
In affected males with X-linked recessive Charcot-Marie-Tooth disease-5
(CMTX5; 311070), Kim et al. (2007) identified mutations in the PRPS1
gene (311850.0009; 311850.0010). The phenotype includes peripheral
neuropathy, sensorineural deafness, and visual impairment. Kim et al.
(2007) used a positional cloning technique and evaluation of candidate
genes known to be expressed in the cochlea to identify the PRPS1 gene
for study. The mutations were shown to result in decreased enzyme
activity; none of the affected individuals had increased uric acid or
gout. Kim et al. (2007) noted that both PRPS1 superactivity and CMT5X
phenotypes share neurologic features.
- Arts Syndrome
Arts syndrome (301835) is an X-linked disorder characterized by mental
retardation, early-onset hypotonia, ataxia, delayed motor development,
hearing impairment, and optic atrophy. Using oligonucleotide microarray
expression profiling of fibroblasts from 2 probands in a Dutch family
with Arts syndrome, de Brouwer et al. (2007) found reduced expression
levels of PRPS1. Sequencing of PRPS1 led to the identification of 2
different missense mutations: L152P (311850.0011) in the Dutch family
and Q133P (311850.0012) in the Australian family. Both mutations
resulted in a loss of PRPS1 activity, as was shown in silico by
molecular modeling and was shown in vitro by enzyme assays in
erythrocytes and fibroblasts from patients. This was in contrast to the
gain-of-function mutations in PRPS1 identified in PRPS-related gout. The
loss-of-function mutations of PRPS1 probably result in impaired purine
biosynthesis, which was supported by the undetectable hypoxanthine in
urine and the reduced uric acid levels in serum from patients. De
Brouwer et al. (2007) suggested that treatment with S-adenosylmethionine
(SAM) theoretically could have therapeutic efficacy to replenish low
levels of purine, and a clinical trial involving the 2 affected
Australian brothers was underway. De Brouwer et al. (2010) reported
preliminary results of the 2 Australian brothers with Arts syndrome.
- X-linked Deafness 1
In a large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss (NSHL) mapping to the DNF2 locus (DFNX1; 304500) on
chromosome Xq22, Liu et al. (2010) analyzed 14 candidate genes and
identified a missense mutation in the PRPS1 gene (D65N; 311850.0013)
that cosegregated with the phenotype. Analysis of the PRPS1 gene in a
British American DNF2 family, previously reported by Tyson et al.
(1996), revealed a different missense mutation (A87T; 311850.0014);
missense mutations were also detected in DFN2 families previously
reported by Manolis et al. (1999) and Cui et al. (2004) (311850.0015 and
311850.0016, respectively). Liu et al. (2010) stated that none of the
mutations were predicted to result in a major structural change in the
PRPS1 protein, which might explain why the disease phenotype was limited
to NSHL.
HISTORY
Wada et al. (1974) and Iinuma et al. (1975) reported a Japanese infant
with mental retardation, hypouricemia, megaloblastic changes in the bone
marrow, and orotic aciduria associated with erythrocyte PRPS deficiency.
Hypsarrhythmia was first observed at 10 months of age and markedly
improved with ACTH therapy concomitant with an increase in red cell PRPS
activity. However, studies in fibroblasts from this patient did not
confirm enzyme deficiency (Becker, 2001).
*FIELD* AV
.0001
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ASN113SER
In a boy with hyperuricemia, sensorineural deafness, ataxia, and
secondary renal insufficiency associated with PRPS1 superactivity
(300661) reported by Becker et al. (1986), Roessler et al. (1991, 1993)
identified a 341A-G transition in the PRPS1 gene, resulting in an
asn113-to-ser (N113S) substitution. Biochemical studies in fibroblasts
were consistent with PRPS superactivity and purine nucleotide
feedback-resistance. The nucleotide sequence of PRPS2 cDNA was normal.
By in vitro functional expression studies in E. coli, Becker et al.
(1995) demonstrated that the N113S mutation resulted in alteration of
the allosteric mechanisms regulating both enzyme inhibition by purine
nucleotides and activation by inorganic phosphate.
.0002
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ASP182HIS
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661) reported by Becker
et al. (1980), Roessler et al. (1991, 1993) identified a 547C-G
transversion in the PRPS1 gene, resulting in an asp182-to-his (D182H)
substitution. His affected mother had gout, uric acid urolithiasis, and
significant hearing loss. The nucleotide sequence of PRPS2 cDNA was
normal. Fibroblast studies of this patient and his mother (Becker et
al., 1980) indicated that the mutant enzyme had both regulatory and
catalytic defects. The enzyme showed 4- to 5-fold greater than normal
resistance to feedback inhibition and, in addition, increased maximal
velocity of the enzyme reaction. The son was hemizygous, and his mother
heterozygous, for the defect.
By in vitro functional expression studies in E. coli, Becker et al.
(1995) demonstrated that the D182H mutation resulted in alteration of
the allosteric mechanisms regulating both enzyme inhibition by purine
nucleotides and activation by inorganic phosphate.
.0003
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ASP51HIS
In a man with gout due to PRPS1 superactivity (300661) resulting from
purine nucleotide feedback-resistance (Zoref et al., 1975), Becker et
al. (1995) identified a 154G-C transversion in the PRPS1 gene, resulting
in an asp51-to-his (D51H) substitution. The patient had recurrent uric
acid lithiasis since age 14 years and severe gouty arthritis since age
20 years. His mother had increased uric acid excretion. In vitro
functional expression studies in E. coli demonstrated that the D51H
mutation resulted in alteration of the allosteric mechanisms regulating
both enzyme inhibition by purine nucleotides and activation by inorganic
phosphate.
.0004
REMOVED FROM DATABASE
.0005
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, LEU128ILE
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661), Becker et al.
(1995) identified a 385C-A transversion in the PRPS1 gene, resulting in
a leu128-to-ile (L128I) substitution. In vitro functional expression
studies in E. coli demonstrated that the L128I mutation resulted in
alteration of the allosteric mechanisms regulating both enzyme
inhibition by purine nucleotides and activation by inorganic phosphate.
.0006
REMOVED FROM DATABASE
.0007
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ALA189VAL
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661), Becker et al.
(1995) identified a 569C-T transition in the PRPS1 gene, resulting in an
ala189-to-val (A189V) substitution. In vitro functional expression
studies in E. coli demonstrated that the A189V mutation resulted in
alteration of the allosteric mechanisms regulating both enzyme
inhibition by purine nucleotides and activation by inorganic phosphate.
.0008
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, HIS192GLN
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661), Becker et al.
(1995) identified a 579C-G transversion in the PRPS1 gene, resulting in
a his192-to-gln (H192Q) substitution. In vitro functional expression
studies in E. coli demonstrated that the H192Q mutation resulted in
alteration of the allosteric mechanisms regulating both enzyme
inhibition by purine nucleotides and activation by inorganic phosphate.
.0009
CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 5
PRPS1, GLU43ASP
In 2 affected brothers with X-linked recessive Charcot-Marie-Tooth
disease-5 (311070), Kim et al. (2007) identified a 129A-C transversion
in exon 2 of the PRPS1 gene, resulting in a glu43-to-asp (E43D)
substitution on the 'flag' region of the N-terminal domain. The affected
residue is highly conserved from zebrafish to human, and the mutation
was not observed in 50 unrelated Caucasian individuals or in 1,103
Korean control chromosomes. None of the affected individuals had
increased uric acid production or gout.
.0010
CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 5
PRPS1, MET115THR
In affected members of a Korean family with CMTX5 (311070), Kim et al.
(2007) identified a 344T-C transition in exon 3 of the PRPS1 gene,
resulting in a met115-to-thr (M115T) substitution in the alpha-helix of
the N-terminal domain. The affected residue is highly conserved from
zebrafish to human, and the mutation was not observed in 1,103 Korean
control chromosomes. In vitro functional expression studies showed that
the M115T mutation resulted in partial loss of enzyme function. None of
the affected individuals had increased uric acid production or gout.
.0011
ARTS SYNDROME
PRPS1, LEU152PRO
In a Dutch family with Arts syndrome (301835) originally reported by
Arts et al. (1993), de Brouwer et al. (2007) found that the disorder was
associated with a 455T-C transition in exon 4 of the PRPS1 gene that
resulted in a leu152-to-pro (L152P) substitution.
.0012
ARTS SYNDROME
PRPS1, GLN133PRO
In an Australian family with Arts syndrome (301835), de Brouwer et al.
(2007) found that the disorder was caused by a 398A-C transversion in
exon 3 of the PRPS1 gene that resulted in a gln133-to-pro (Q133P)
substitution. Enzyme assays and molecular modeling demonstrated loss of
function of the mutant protein.
.0013
DEAFNESS, X-LINKED 1
PRPS1, ASP65ASN
In affected members of a large 5-generation Chinese family segregating
X-linked deafness-1 (304500), Liu et al. (2010) identified a 193G-A
transition in exon 2 of the PRPS1 gene, resulting in an asp65-to-asn
(D65N) substitution at a highly conserved residue in the alpha helix at
the N terminus. The mutation was not found in 1,025 ethnically matched
control chromosomes. Enzymatic activity assays showed reductions of
PRPS1 activity in patient erythrocytes of approximately 40 to 70% and in
patient fibroblasts of approximately 50 to 60% compared to controls.
.0014
DEAFNESS, X-LINKED 1
PRPS1, ALA87THR
In affected members of a British American family segregating X-linked
deafness-1 (304500), previously reported by Tyson et al. (1996), Liu et
al. (2010) identified a 259G-A transition in exon 2 of the PRPS1 gene,
resulting in an ala87-to-thr (A87T) substitution at a highly conserved
residue. The mutation was not found in 1,475 Chinese control chromosomes
or 450 chromosomes of European descent.
.0015
DEAFNESS, X-LINKED 1
PRPS1, GLY306ARG
In affected members of an American family segregating X-linked
deafness-1 (304500), previously reported by Manolis et al. (1999), Liu
et al. (2010) identified a 916G-A transition in exon 7 of the PRPS1
gene, resulting in a gly306-to-arg (G306R) substitution at a highly
conserved residue. The mutation was not found in 1,475 Chinese control
chromosomes or 450 chromosomes of European descent.
.0016
DEAFNESS, X-LINKED 1
PRPS1, ILE290THR
In affected members from a Chinese family segregating X-linked
postlingual nonsyndromic hearing loss (DFNX1; 304500), previously
reported by Cui et al. (2004), Liu et al. (2010) identified an 869T-C
transition in exon 7 of the PRPS1 gene, resulting in an ile290-to-thr
(I290T) substitution at a highly conserved residue. The mutation was not
found in 1,025 ethnically matched control chromosomes.
.0017
ARTS SYNDROME AND PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, VAL142LEU
In a boy with a complex phenotype comprising Arts syndrome and PRPS1
superactivity (see 301835), Moran et al. (2012) identified a 424G-C
transversion in exon 4 of the PRPS1 gene, resulting in a val142-to-leu
(V142L) substitution at a highly conserved residue. Both the mother and
grandmother were heterozygous for the mutation, which was not found in
202 control alleles. The patient had developmental delay, hypotonia,
areflexia, motor neuropathy, sensorineural hearing loss, and a Chiari I
malformation. Laboratory studies showed increased serum uric acid and
increased urinary hypoxanthine consistent with PRPS1 superactivity, but
he did not have gout. In addition, he had recurrent infections and early
death at age 27 months from infection, consistent with Arts syndrome. A
maternal uncle with similar symptoms had died of pneumonia at age 2.
Molecular modeling predicted that the substitution would disrupt
allosteric sites involved in inhibition of PRPS1, resulting in a gain of
enzyme function, and the ATP-binding site, resulting in a loss of enzyme
function. Patient fibroblasts showed normal PRPP synthetase activity,
whereas erythrocytes showed a loss of enzyme activity, suggesting that
the effect of the V142L mutation on protein activity depends on cell
type. Moran et al. (2012) postulated a gain-of-function effect in
proliferating cells and a loss-of-function effect in postmitotic cells.
The report indicated that PRPS1 missense mutations can cause a
continuous spectrum of features ranging from progressive nonsyndromic
postlingual hearing impairment to uric acid overproduction, neuropathy,
and recurrent infections depending on the functional sites affected.
*FIELD* SA
Lebo and Martin (1978)
*FIELD* RF
1. Arts, W. F. M.; Loonen, M. C. B.; Sengers, R. C. A.; Slooff, J.
L.: X-linked ataxia, weakness, deafness, and loss of vision in early
childhood with a fatal course. Ann. Neurol. 33: 535-539, 1993.
2. Becker, M. A.: Hyperuricemia and Gout.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. 8th ed. New York: McGraw-Hill
2001. P. 2625.
3. Becker, M. A.; Heidler, S. A.; Bell, G. I.; Seino, S.; Le Beau,
M. M.; Westbrook, C. A.; Neuman, W.; Shapiro, L. J.; Mohandas, T.
K.; Roessler, B. J.; Palella, T. D.: Cloning of cDNAs for human phosphoribosylpyrophosphate
synthetases 1 and 2 and X chromosome localization of PRPS1 and PRPS2
genes. Genomics 8: 555-561, 1990.
4. Becker, M. A.; Losman, M. J.; Wilson, J.; Simmonds, H. A.: Superactivity
of human phosphoribosyl pyrophosphate synthetase due to altered regulation
by nucleotide inhibitors and inorganic phosphate. Biochim. Biophys.
Acta 882: 168-176, 1986.
5. Becker, M. A.; Raivio, K. O.; Bakay, B.; Adams, W. B.; Nyhan, W.
L.: Variant human phosphoribosylpyrophosphate synthetase altered
in regulatory and catalytic functions. J. Clin. Invest. 65: 109-120,
1980.
6. Becker, M. A.; Smith, P. R.; Taylor, W.; Mustafi, R.; Switzer,
R. L.: The genetic and functional basis of purine nucleotide feedback-resistant
phosphoribosylpyrophosphate synthetase superactivity. J. Clin. Invest. 96:
2133-2141, 1995.
7. Becker, M. A.; Yen, R. C. K.; Goss, S. J.; Seegmiller, J. E.; Itkin,
P.; Lazar, C.; Adams, W. B.: Localization of the structural gene
for human phosphoribosylpyrophosphate synthetase on the X-chromosome.
(Abstract) Clin. Res. 26: 500A, 1978.
8. Becker, M. A.; Yen, R. C. K.; Itkin, P.; Goss, S. J.; Seegmiller,
J. E.; Bakay, B.: Regional localization of the gene for human phosphoribosylpyrophosphate
synthetase on the X-chromosome. Science 203: 1016-1019, 1979.
9. Cui, B.; Zhang, H.; Lu, Y.; Zhong, W.; Pei, G.; Kong, X.; Hu, L.
: Refinement of the locus for non-syndromic sensorineural deafness
(DFN2) J. Genet. 83: 35-38, 2004.
10. de Brouwer, A. P. M.; van Bokhoven, H.; Nabuurs, S. B.; Arts,
W. F.; Christodoulou, J.; Duley, J.: PRPS1 mutations: four distinct
syndromes and potential treatment. Am. J. Hum. Genet. 86: 506-518,
2010.
11. de Brouwer, A. P. M.; Williams, K. L.; Duley, J. A.; van Kuilenburg,
A. B. P.; Nabuurs, S. B.; Egmont-Petersen, M.; Lugtenberg, D.; Zoetekouw,
L.; Banning, M. J. G.; Roeffen, M.; Hamel, B. C. J.; Weaving, L.;
Ouvrier, R. A.; Donald, J. A.; Wevers, R. A.; Christodoulou, J.; van
Bokhoven, H.: Arts syndrome is caused by loss-of-function mutations
in PRPS1. Am. J. Hum. Genet. 81: 507-518, 2007.
12. Iinuma, K.; Wada, Y.; Onuma, A.; Tanabu, M.: Electroencephalographic
study of an infant with phosphoribosylpyrophosphate synthetase deficiency. Tohoku
J. Exp. Med. 116: 53-55, 1975.
13. Kim, H.-J.; Sohn, K.-M.; Shy, M. E.; Krajewski, K. M.; Hwang,
M.; Park, J.-H.; Jang, S.-Y.; Won, H.-H.; Choi, B.-O.; Hong, S. H.;
Kim, B.-J.; Suh, Y.-L.; Ki, C.-S.; Lee, S.-Y.; Kim, S.-H.; Kim, J.-W.
: Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate
synthetase enzyme critical for nucleotide biosynthesis, cause hereditary
peripheral neuropathy with hearing loss and optic neuropathy (CMT5X). Am.
J. Hum. Genet. 81: 552-558, 2007.
14. Lebo, R. V.; Martin, D. W., Jr.: Electrophoretic heterogeneity
of 5-phosphoribosyl-1-pyrophosphate synthetase within and among humans. Biochem.
Genet. 16: 905-916, 1978.
15. Liu, X.; Han, D.; Li, J.; Han, B.; Ouyang, X.; Cheng, J.; Li,
X.; Jin, Z.; Wang, Y.; Bitner-Glindzicz, M.; Kong, X.; Xu, H.; and
10 others: Loss-of-function mutations in the PRPS1 gene cause a
type of nonsyndromic X-linked sensorineural deafness, DFN2. Am. J.
Hum. Genet. 86: 65-71, 2010.
16. Manolis, E. N.; Eavey, R. D.; Sangwatanaroj, S.; Halpin, C.; Rosenbaum,
S.; Watkins, H.; Jarcho, J.; Seidman, C. E.; Seidman, J. G.: Hereditary
postlingual sensorineural hearing loss mapping to chromosome Xq21. Am.
J. Otol. 20: 621-626, 1999.
17. Moran, R.; Kuilenburg, A. B. P.; Duley, J.; Nabuurs, S. B.; Retno-Fitri,
A.; Christodoulou, J.; Roelofsen, J.; Yntema, H. G.; Friedman, N.
R.; van Bokhoven, H.; de Brouwer, A. P. M.: Phosphoribosylpyrophosphate
synthetase superactivity and recurrent infections is caused by a p.val142-to-leu
mutation in PRS-I. Am. J. Med. Genet. 158A: 455-460, 2012.
18. Roessler, B. J.; Bell, G.; Heidler, S.; Seino, S.; Becker, M.;
Palella, T. D.: Cloning of two distinct copies of human phosphoribosylpyrophosphate
synthetase cDNA. Nucleic Acids Res. 18: 193 only, 1990.
19. Roessler, B. J.; Nosal, J. M.; Smith, P. R.; Heidler, S. A.; Palella,
T. D.; Switzer, R. L.; Becker, M. A.: Human X-linked phosphoribosylpyrophosphate
synthetase superactivity is associated with distinct point mutations
in the PRPS1 gene. J. Biol. Chem. 268: 26476-26481, 1993.
20. Roessler, B. J.; Palella, T. D.; Heidler, S.; Becker, M. A.:
Identification of distinct PRPS1 mutations in two patients with X-linked
phosphoribosylpyrophosphate synthetase superactivity. (Abstract) Clin.
Res. 39: 267A, 1991.
21. Taira, M.; Iizasa, T.; Yamada, K.; Shimada, H.; Tatibana, M.:
Tissue-differential expression of two distinct genes for phosphoribosyl
pyrophosphate synthetase and existence of the testis-specific transcript. Biochim.
Biophys. Acta 1007: 203-208, 1989.
22. Tyson, J.; Bellman, S.; Newton, V.; Simpson, P.; Malcolm, S.;
Pembrey, M. E.; Bitner-Glindzicz, M.: Mapping of DFN2 to Xq22. Hum.
Molec. Genet. 5: 2055-2060, 1996.
23. Wada, Y.; Nishimura, Y.; Tanabu, M.; Yoshimura, Y.; Iinuma, K.;
Yoshida, T.; Arakawa, T.: Hypouricemic, mentally retarded infant
with a defect of 5-phosphoribosyl-1-pyrophosphate synthetase of erythrocytes. Tohoku
J. Exp. Med. 113: 149-157, 1974.
24. Zoref, E.; De Vries, A.; Sperling, O.: Mutant feedback-resistant
phosphoribosylpyrophosphate synthetase associated with purine overproduction
and gout: phosphoribosylpyrophosphate and purine metabolism in cultured
fibroblasts. J. Clin. Invest. 56: 1093-1099, 1975.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/9/2012
Cassandra L. Kniffin - updated: 4/30/2010
Marla J. F. O'Neill - updated: 2/26/2010
Patricia A. Hartz - updated: 10/24/2007
Victor A. McKusick - updated: 8/22/2007
Cassandra L. Kniffin - reorganized: 8/17/2007
Cassandra L. Kniffin - updated: 8/16/2007
Rebekah S. Rasooly - updated: 2/26/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 04/20/2012
alopez: 4/13/2012
alopez: 4/12/2012
terry: 4/10/2012
ckniffin: 4/9/2012
carol: 4/12/2011
wwang: 5/4/2010
ckniffin: 4/30/2010
terry: 4/2/2010
carol: 2/26/2010
mgross: 10/30/2007
terry: 10/24/2007
alopez: 8/22/2007
carol: 8/17/2007
ckniffin: 8/16/2007
alopez: 9/10/2004
terry: 6/25/2004
psherman: 3/1/1999
psherman: 2/26/1999
dkim: 7/7/1998
terry: 11/18/1996
terry: 11/4/1996
mark: 2/2/1996
terry: 1/26/1996
terry: 5/10/1994
warfield: 4/20/1994
carol: 4/11/1994
mimadm: 2/28/1994
carol: 12/16/1992
carol: 12/3/1992
*RECORD*
*FIELD* NO
311850
*FIELD* TI
*311850 PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1
*FIELD* TX
DESCRIPTION
Phosphoribosylpyrophosphate synthetase (PRPS; EC 2.7.6.1) catalyzes the
read morephosphoribosylation of ribose 5-phosphate to
5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and
salvage pathways of purine and pyrimidine biosynthesis (Roessler et al.,
1990). Three PRPS genes have been identified: the widely expressed PRPS1
and PRPS2 (311860) genes, which map to chromosome Xq22-q24 and Xp22,
respectively, and PRPS3 (PRPS1L1; 611566), which maps to chromosome 7
and appears to be transcribed only in testis (Becker, 2001).
CLONING
Roessler et al. (1990) isolated a partial clone corresponding to the
PRPS1 gene from a human lymphoblast cDNA library. The deduced PRPS1
protein has 318 amino acids and shares 95% amino acid homology with
PRPS2. Becker et al. (1990) also cloned the PRPS1 gene and detected a
2.3-kb mRNA transcript.
By Northern blot analysis using rat Prps1 as probe, Taira et al. (1989)
detected a 2.3-kb transcript in human adipose tissue, testis, and
placenta and in 2 human cell lines.
Kim et al. (2007) demonstrated that the PRPS1 amino acid sequence shows
an exceptionally high degree of conservation, with homologies greater
than 95% across different species from zebrafish to human.
GENE STRUCTURE
The PRPS1 gene spans over 30 kb and contains 7 exons (Becker, 2001).
MAPPING
By the Goss-Harris method, Becker et al. (1978) concluded that the order
of loci on chromosome Xq is G6PD (305900)--HPRT1
(308000)--PRPS1--alpha-GAL (GLA; 300644)--PGK1 (311800)--centromere.
Becker et al. (1979) assigned the PRPS1 locus to a position between the
GLA and HPRT1 loci, particularly close to the latter, and discussed the
functional significance of the proximity of the genes for their
biochemically related functions.
Becker et al. (1990) mapped PRPS1 to Xq22-q24 by a combination of in
situ hybridization and study of human/rodent somatic cell hybrids.
- Pseudogene
By in situ chromosomal hybridization, Becker et al. (1990) identified a
PRPS1-related gene or pseudogene (PRPS1L2) on chromosome 9q33-q34.
MOLECULAR GENETICS
De Brouwer et al. (2010) provided a review of the clinical and molecular
features of the 4 distinct syndromes caused by mutation in the PRPS1
gene: PRPS1 superactivity (300661), X-linked Charcot-Marie-Tooth
disease-5 (CMTX5; 311070), Arts syndrome (301835), and isolated X-linked
sensorineural deafness (304500). The neurologic phenotype in all 4
PRPS1-related disorders seems to result primarily from reduced levels of
GTP and possibly other purine nucleotides including ATP, suggesting that
these disorders belong to the same disease spectrum. Preliminary results
of S-adenosylmethionine (SAM) supplementation in 2 Australian brothers
with Arts syndrome revealed some improvement of their condition,
suggesting that SAM supplementation could potentially alleviate some of
the symptoms of patients with PRPS1 spectrum diseases by replenishing
purine nucleotides.
- Phosphoribosylpyrophosphate Synthetase Superactivity
In patients with phosphoribosylpyrophosphate synthetase superactivity
(300661), Roessler et al. (1991, 1993) and Becker et al. (1995)
identified mutations in the PRPS1 gene (311850.0001-311850.0008). All
patients except 1 had hyperuricemia, neurodevelopmental abnormalities,
and sensorineural deafness; the other patient had only hyperuricemia and
gout. Functional expression studies of all mutations showed that enzyme
overactivity was due to alteration of allosteric feedback mechanisms.
- Charcot-Marie-Tooth Disease, X-linked Recessive, 5
In affected males with X-linked recessive Charcot-Marie-Tooth disease-5
(CMTX5; 311070), Kim et al. (2007) identified mutations in the PRPS1
gene (311850.0009; 311850.0010). The phenotype includes peripheral
neuropathy, sensorineural deafness, and visual impairment. Kim et al.
(2007) used a positional cloning technique and evaluation of candidate
genes known to be expressed in the cochlea to identify the PRPS1 gene
for study. The mutations were shown to result in decreased enzyme
activity; none of the affected individuals had increased uric acid or
gout. Kim et al. (2007) noted that both PRPS1 superactivity and CMT5X
phenotypes share neurologic features.
- Arts Syndrome
Arts syndrome (301835) is an X-linked disorder characterized by mental
retardation, early-onset hypotonia, ataxia, delayed motor development,
hearing impairment, and optic atrophy. Using oligonucleotide microarray
expression profiling of fibroblasts from 2 probands in a Dutch family
with Arts syndrome, de Brouwer et al. (2007) found reduced expression
levels of PRPS1. Sequencing of PRPS1 led to the identification of 2
different missense mutations: L152P (311850.0011) in the Dutch family
and Q133P (311850.0012) in the Australian family. Both mutations
resulted in a loss of PRPS1 activity, as was shown in silico by
molecular modeling and was shown in vitro by enzyme assays in
erythrocytes and fibroblasts from patients. This was in contrast to the
gain-of-function mutations in PRPS1 identified in PRPS-related gout. The
loss-of-function mutations of PRPS1 probably result in impaired purine
biosynthesis, which was supported by the undetectable hypoxanthine in
urine and the reduced uric acid levels in serum from patients. De
Brouwer et al. (2007) suggested that treatment with S-adenosylmethionine
(SAM) theoretically could have therapeutic efficacy to replenish low
levels of purine, and a clinical trial involving the 2 affected
Australian brothers was underway. De Brouwer et al. (2010) reported
preliminary results of the 2 Australian brothers with Arts syndrome.
- X-linked Deafness 1
In a large 5-generation Chinese family segregating X-linked nonsyndromic
hearing loss (NSHL) mapping to the DNF2 locus (DFNX1; 304500) on
chromosome Xq22, Liu et al. (2010) analyzed 14 candidate genes and
identified a missense mutation in the PRPS1 gene (D65N; 311850.0013)
that cosegregated with the phenotype. Analysis of the PRPS1 gene in a
British American DNF2 family, previously reported by Tyson et al.
(1996), revealed a different missense mutation (A87T; 311850.0014);
missense mutations were also detected in DFN2 families previously
reported by Manolis et al. (1999) and Cui et al. (2004) (311850.0015 and
311850.0016, respectively). Liu et al. (2010) stated that none of the
mutations were predicted to result in a major structural change in the
PRPS1 protein, which might explain why the disease phenotype was limited
to NSHL.
HISTORY
Wada et al. (1974) and Iinuma et al. (1975) reported a Japanese infant
with mental retardation, hypouricemia, megaloblastic changes in the bone
marrow, and orotic aciduria associated with erythrocyte PRPS deficiency.
Hypsarrhythmia was first observed at 10 months of age and markedly
improved with ACTH therapy concomitant with an increase in red cell PRPS
activity. However, studies in fibroblasts from this patient did not
confirm enzyme deficiency (Becker, 2001).
*FIELD* AV
.0001
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ASN113SER
In a boy with hyperuricemia, sensorineural deafness, ataxia, and
secondary renal insufficiency associated with PRPS1 superactivity
(300661) reported by Becker et al. (1986), Roessler et al. (1991, 1993)
identified a 341A-G transition in the PRPS1 gene, resulting in an
asn113-to-ser (N113S) substitution. Biochemical studies in fibroblasts
were consistent with PRPS superactivity and purine nucleotide
feedback-resistance. The nucleotide sequence of PRPS2 cDNA was normal.
By in vitro functional expression studies in E. coli, Becker et al.
(1995) demonstrated that the N113S mutation resulted in alteration of
the allosteric mechanisms regulating both enzyme inhibition by purine
nucleotides and activation by inorganic phosphate.
.0002
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ASP182HIS
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661) reported by Becker
et al. (1980), Roessler et al. (1991, 1993) identified a 547C-G
transversion in the PRPS1 gene, resulting in an asp182-to-his (D182H)
substitution. His affected mother had gout, uric acid urolithiasis, and
significant hearing loss. The nucleotide sequence of PRPS2 cDNA was
normal. Fibroblast studies of this patient and his mother (Becker et
al., 1980) indicated that the mutant enzyme had both regulatory and
catalytic defects. The enzyme showed 4- to 5-fold greater than normal
resistance to feedback inhibition and, in addition, increased maximal
velocity of the enzyme reaction. The son was hemizygous, and his mother
heterozygous, for the defect.
By in vitro functional expression studies in E. coli, Becker et al.
(1995) demonstrated that the D182H mutation resulted in alteration of
the allosteric mechanisms regulating both enzyme inhibition by purine
nucleotides and activation by inorganic phosphate.
.0003
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ASP51HIS
In a man with gout due to PRPS1 superactivity (300661) resulting from
purine nucleotide feedback-resistance (Zoref et al., 1975), Becker et
al. (1995) identified a 154G-C transversion in the PRPS1 gene, resulting
in an asp51-to-his (D51H) substitution. The patient had recurrent uric
acid lithiasis since age 14 years and severe gouty arthritis since age
20 years. His mother had increased uric acid excretion. In vitro
functional expression studies in E. coli demonstrated that the D51H
mutation resulted in alteration of the allosteric mechanisms regulating
both enzyme inhibition by purine nucleotides and activation by inorganic
phosphate.
.0004
REMOVED FROM DATABASE
.0005
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, LEU128ILE
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661), Becker et al.
(1995) identified a 385C-A transversion in the PRPS1 gene, resulting in
a leu128-to-ile (L128I) substitution. In vitro functional expression
studies in E. coli demonstrated that the L128I mutation resulted in
alteration of the allosteric mechanisms regulating both enzyme
inhibition by purine nucleotides and activation by inorganic phosphate.
.0006
REMOVED FROM DATABASE
.0007
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, ALA189VAL
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661), Becker et al.
(1995) identified a 569C-T transition in the PRPS1 gene, resulting in an
ala189-to-val (A189V) substitution. In vitro functional expression
studies in E. coli demonstrated that the A189V mutation resulted in
alteration of the allosteric mechanisms regulating both enzyme
inhibition by purine nucleotides and activation by inorganic phosphate.
.0008
PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, HIS192GLN
In a boy with hyperuricemia, mental retardation, and sensorineural
deafness associated with PRPS1 superactivity (300661), Becker et al.
(1995) identified a 579C-G transversion in the PRPS1 gene, resulting in
a his192-to-gln (H192Q) substitution. In vitro functional expression
studies in E. coli demonstrated that the H192Q mutation resulted in
alteration of the allosteric mechanisms regulating both enzyme
inhibition by purine nucleotides and activation by inorganic phosphate.
.0009
CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 5
PRPS1, GLU43ASP
In 2 affected brothers with X-linked recessive Charcot-Marie-Tooth
disease-5 (311070), Kim et al. (2007) identified a 129A-C transversion
in exon 2 of the PRPS1 gene, resulting in a glu43-to-asp (E43D)
substitution on the 'flag' region of the N-terminal domain. The affected
residue is highly conserved from zebrafish to human, and the mutation
was not observed in 50 unrelated Caucasian individuals or in 1,103
Korean control chromosomes. None of the affected individuals had
increased uric acid production or gout.
.0010
CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 5
PRPS1, MET115THR
In affected members of a Korean family with CMTX5 (311070), Kim et al.
(2007) identified a 344T-C transition in exon 3 of the PRPS1 gene,
resulting in a met115-to-thr (M115T) substitution in the alpha-helix of
the N-terminal domain. The affected residue is highly conserved from
zebrafish to human, and the mutation was not observed in 1,103 Korean
control chromosomes. In vitro functional expression studies showed that
the M115T mutation resulted in partial loss of enzyme function. None of
the affected individuals had increased uric acid production or gout.
.0011
ARTS SYNDROME
PRPS1, LEU152PRO
In a Dutch family with Arts syndrome (301835) originally reported by
Arts et al. (1993), de Brouwer et al. (2007) found that the disorder was
associated with a 455T-C transition in exon 4 of the PRPS1 gene that
resulted in a leu152-to-pro (L152P) substitution.
.0012
ARTS SYNDROME
PRPS1, GLN133PRO
In an Australian family with Arts syndrome (301835), de Brouwer et al.
(2007) found that the disorder was caused by a 398A-C transversion in
exon 3 of the PRPS1 gene that resulted in a gln133-to-pro (Q133P)
substitution. Enzyme assays and molecular modeling demonstrated loss of
function of the mutant protein.
.0013
DEAFNESS, X-LINKED 1
PRPS1, ASP65ASN
In affected members of a large 5-generation Chinese family segregating
X-linked deafness-1 (304500), Liu et al. (2010) identified a 193G-A
transition in exon 2 of the PRPS1 gene, resulting in an asp65-to-asn
(D65N) substitution at a highly conserved residue in the alpha helix at
the N terminus. The mutation was not found in 1,025 ethnically matched
control chromosomes. Enzymatic activity assays showed reductions of
PRPS1 activity in patient erythrocytes of approximately 40 to 70% and in
patient fibroblasts of approximately 50 to 60% compared to controls.
.0014
DEAFNESS, X-LINKED 1
PRPS1, ALA87THR
In affected members of a British American family segregating X-linked
deafness-1 (304500), previously reported by Tyson et al. (1996), Liu et
al. (2010) identified a 259G-A transition in exon 2 of the PRPS1 gene,
resulting in an ala87-to-thr (A87T) substitution at a highly conserved
residue. The mutation was not found in 1,475 Chinese control chromosomes
or 450 chromosomes of European descent.
.0015
DEAFNESS, X-LINKED 1
PRPS1, GLY306ARG
In affected members of an American family segregating X-linked
deafness-1 (304500), previously reported by Manolis et al. (1999), Liu
et al. (2010) identified a 916G-A transition in exon 7 of the PRPS1
gene, resulting in a gly306-to-arg (G306R) substitution at a highly
conserved residue. The mutation was not found in 1,475 Chinese control
chromosomes or 450 chromosomes of European descent.
.0016
DEAFNESS, X-LINKED 1
PRPS1, ILE290THR
In affected members from a Chinese family segregating X-linked
postlingual nonsyndromic hearing loss (DFNX1; 304500), previously
reported by Cui et al. (2004), Liu et al. (2010) identified an 869T-C
transition in exon 7 of the PRPS1 gene, resulting in an ile290-to-thr
(I290T) substitution at a highly conserved residue. The mutation was not
found in 1,025 ethnically matched control chromosomes.
.0017
ARTS SYNDROME AND PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
PRPS1, VAL142LEU
In a boy with a complex phenotype comprising Arts syndrome and PRPS1
superactivity (see 301835), Moran et al. (2012) identified a 424G-C
transversion in exon 4 of the PRPS1 gene, resulting in a val142-to-leu
(V142L) substitution at a highly conserved residue. Both the mother and
grandmother were heterozygous for the mutation, which was not found in
202 control alleles. The patient had developmental delay, hypotonia,
areflexia, motor neuropathy, sensorineural hearing loss, and a Chiari I
malformation. Laboratory studies showed increased serum uric acid and
increased urinary hypoxanthine consistent with PRPS1 superactivity, but
he did not have gout. In addition, he had recurrent infections and early
death at age 27 months from infection, consistent with Arts syndrome. A
maternal uncle with similar symptoms had died of pneumonia at age 2.
Molecular modeling predicted that the substitution would disrupt
allosteric sites involved in inhibition of PRPS1, resulting in a gain of
enzyme function, and the ATP-binding site, resulting in a loss of enzyme
function. Patient fibroblasts showed normal PRPP synthetase activity,
whereas erythrocytes showed a loss of enzyme activity, suggesting that
the effect of the V142L mutation on protein activity depends on cell
type. Moran et al. (2012) postulated a gain-of-function effect in
proliferating cells and a loss-of-function effect in postmitotic cells.
The report indicated that PRPS1 missense mutations can cause a
continuous spectrum of features ranging from progressive nonsyndromic
postlingual hearing impairment to uric acid overproduction, neuropathy,
and recurrent infections depending on the functional sites affected.
*FIELD* SA
Lebo and Martin (1978)
*FIELD* RF
1. Arts, W. F. M.; Loonen, M. C. B.; Sengers, R. C. A.; Slooff, J.
L.: X-linked ataxia, weakness, deafness, and loss of vision in early
childhood with a fatal course. Ann. Neurol. 33: 535-539, 1993.
2. Becker, M. A.: Hyperuricemia and Gout.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. II. 8th ed. New York: McGraw-Hill
2001. P. 2625.
3. Becker, M. A.; Heidler, S. A.; Bell, G. I.; Seino, S.; Le Beau,
M. M.; Westbrook, C. A.; Neuman, W.; Shapiro, L. J.; Mohandas, T.
K.; Roessler, B. J.; Palella, T. D.: Cloning of cDNAs for human phosphoribosylpyrophosphate
synthetases 1 and 2 and X chromosome localization of PRPS1 and PRPS2
genes. Genomics 8: 555-561, 1990.
4. Becker, M. A.; Losman, M. J.; Wilson, J.; Simmonds, H. A.: Superactivity
of human phosphoribosyl pyrophosphate synthetase due to altered regulation
by nucleotide inhibitors and inorganic phosphate. Biochim. Biophys.
Acta 882: 168-176, 1986.
5. Becker, M. A.; Raivio, K. O.; Bakay, B.; Adams, W. B.; Nyhan, W.
L.: Variant human phosphoribosylpyrophosphate synthetase altered
in regulatory and catalytic functions. J. Clin. Invest. 65: 109-120,
1980.
6. Becker, M. A.; Smith, P. R.; Taylor, W.; Mustafi, R.; Switzer,
R. L.: The genetic and functional basis of purine nucleotide feedback-resistant
phosphoribosylpyrophosphate synthetase superactivity. J. Clin. Invest. 96:
2133-2141, 1995.
7. Becker, M. A.; Yen, R. C. K.; Goss, S. J.; Seegmiller, J. E.; Itkin,
P.; Lazar, C.; Adams, W. B.: Localization of the structural gene
for human phosphoribosylpyrophosphate synthetase on the X-chromosome.
(Abstract) Clin. Res. 26: 500A, 1978.
8. Becker, M. A.; Yen, R. C. K.; Itkin, P.; Goss, S. J.; Seegmiller,
J. E.; Bakay, B.: Regional localization of the gene for human phosphoribosylpyrophosphate
synthetase on the X-chromosome. Science 203: 1016-1019, 1979.
9. Cui, B.; Zhang, H.; Lu, Y.; Zhong, W.; Pei, G.; Kong, X.; Hu, L.
: Refinement of the locus for non-syndromic sensorineural deafness
(DFN2) J. Genet. 83: 35-38, 2004.
10. de Brouwer, A. P. M.; van Bokhoven, H.; Nabuurs, S. B.; Arts,
W. F.; Christodoulou, J.; Duley, J.: PRPS1 mutations: four distinct
syndromes and potential treatment. Am. J. Hum. Genet. 86: 506-518,
2010.
11. de Brouwer, A. P. M.; Williams, K. L.; Duley, J. A.; van Kuilenburg,
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*FIELD* CN
Cassandra L. Kniffin - updated: 4/9/2012
Cassandra L. Kniffin - updated: 4/30/2010
Marla J. F. O'Neill - updated: 2/26/2010
Patricia A. Hartz - updated: 10/24/2007
Victor A. McKusick - updated: 8/22/2007
Cassandra L. Kniffin - reorganized: 8/17/2007
Cassandra L. Kniffin - updated: 8/16/2007
Rebekah S. Rasooly - updated: 2/26/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 04/20/2012
alopez: 4/13/2012
alopez: 4/12/2012
terry: 4/10/2012
ckniffin: 4/9/2012
carol: 4/12/2011
wwang: 5/4/2010
ckniffin: 4/30/2010
terry: 4/2/2010
carol: 2/26/2010
mgross: 10/30/2007
terry: 10/24/2007
alopez: 8/22/2007
carol: 8/17/2007
ckniffin: 8/16/2007
alopez: 9/10/2004
terry: 6/25/2004
psherman: 3/1/1999
psherman: 2/26/1999
dkim: 7/7/1998
terry: 11/18/1996
terry: 11/4/1996
mark: 2/2/1996
terry: 1/26/1996
terry: 5/10/1994
warfield: 4/20/1994
carol: 4/11/1994
mimadm: 2/28/1994
carol: 12/16/1992
carol: 12/3/1992