RBCC Red Blood Cell Collection

ADSL (AMPS) [Confidence: high (present in two of the MS resources)]
Adenylosuccinate lyase; ASL; 4.3.2.2 (Adenylosuccinase; ASase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00026904
IPI00026904 Splice Isoform 1 Of Adenylosuccinate lyase Splice Isoform 1 Of Adenylosuccinate lyase membrane 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 1 n/a n/a cytoplasmic splice isoforms 1 and 2 found at its expected molecular weight found at molecular weight

UniProt P30566
ID PUR8_HUMAN Reviewed; 484 AA.
AC P30566; B0QY76; O75495; Q5TI34;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-MAY-2000, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Adenylosuccinate lyase;
DE Short=ASL;
DE EC=4.3.2.2;
DE AltName: Full=Adenylosuccinase;
DE Short=ASase;
GN Name=ADSL; Synonyms=AMPS;
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] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=8404037;
RA Fon E.A., Demczuk S., Delattre O., Thomas G., Rouleau G.A.;
RT "Mapping of the human adenylosuccinate lyase (ADSL) gene to chromosome
RT 22q13.1-->q13.2.";
RL Cytogenet. Cell Genet. 64:201-203(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANTS ADSL
RP DEFICIENCY VAL-3; HIS-114; GLN-190; CYS-194; ASN-268; HIS-426 AND
RP ASN-430.
RC TISSUE=Skeletal muscle;
RX PubMed=10888601; DOI=10.1093/hmg/9.10.1501;
RA Kmoch S., Hartmannova H., Stiburkova B., Krijt J., Zikanova M.,
RA Sebesta I.;
RT "Human adenylosuccinate lyase (ADSL), cloning and characterization of
RT full-length cDNA and its isoform, gene structure and molecular basis
RT for ADSL deficiency in six patients.";
RL Hum. Mol. Genet. 9:1501-1513(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Eye;
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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-484 (ISOFORM 1), AND VARIANT ADSL
RP DEFICIENCY PRO-438.
RX PubMed=1302001; DOI=10.1038/ng0492-59;
RA Stone R.L., Aimi J., Barshop B.A., Jaeken J., van den Berghe G.,
RA Zalkin H., Dixon J.E.;
RT "A mutation in adenylosuccinate lyase associated with mental
RT retardation and autistic features.";
RL Nat. Genet. 1:59-63(1992).
RN [8]
RP PROTEIN SEQUENCE OF 2-20 AND 235-245, CLEAVAGE OF INITIATOR
RP METHIONINE, ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Ramsay A., Leung H.Y.;
RL Submitted (JUN-2009) to UniProtKB.
RN [9]
RP CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=16973378; DOI=10.1016/j.pep.2006.07.023;
RA Lee P., Colman R.F.;
RT "Expression, purification, and characterization of stable, recombinant
RT human adenylosuccinate lyase.";
RL Protein Expr. Purif. 51:227-234(2007).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-147 AND LYS-295, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEXES WITH SUBSTRATE;
RP FUMARATE AND AMP.
RG Structural genomics consortium (SGC);
RT "Human adenylosuccinate lyase in complex with its substrate N6-(1,2-
RT dicarboxyethyl)-AMP, and its products AMP and fumarate.";
RL Submitted (SEP-2007) to the PDB data bank.
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF WILD-TYPE AND VARIANT ADSL
RP DEFICIENCY CYS-303, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT
RP ADSL DEFICIENCY CYS-303, ACTIVE SITE, ENZYME REGULATION, AND SUBUNIT.
RX PubMed=22812634; DOI=10.1021/bi300796y;
RA Ray S.P., Deaton M.K., Capodagli G.C., Calkins L.A., Sawle L.,
RA Ghosh K., Patterson D., Pegan S.D.;
RT "Structural and biochemical characterization of human adenylosuccinate
RT lyase (ADSL) and the R303C ADSL deficiency-associated mutation.";
RL Biochemistry 51:6701-6713(2012).
RN [15]
RP VARIANT ADSL DEFICIENCY HIS-426.
RX PubMed=9266401; DOI=10.1023/A:1005323512982;
RA Maaswinkel-Mooij P.D., Laan L.A.E.M., Onkenhout W., Brouwer O.F.,
RA Jaeken J., Poorthuis B.J.H.M.;
RT "Adenylosuccinase deficiency presenting with epilepsy in early
RT infancy.";
RL J. Inherit. Metab. Dis. 20:606-607(1997).
RN [16]
RP VARIANTS ADSL DEFICIENCY ALA-100 AND TYR-422.
RX PubMed=9545543; DOI=10.1016/S0925-4439(97)00086-0;
RA Verginelli D., Luckow B., Crifo C., Salerno C., Gross M.;
RT "Identification of new mutations in the adenylosuccinate lyase gene
RT associated with impaired enzyme activity in lymphocytes and red blood
RT cells.";
RL Biochim. Biophys. Acta 1406:81-84(1998).
RN [17]
RP VARIANTS ADSL DEFICIENCY VAL-72; TRP-141; GLN-190; GLU-246; CYS-303;
RP ARG-395 AND HIS-426.
RX PubMed=10090474;
RX DOI=10.1002/(SICI)1098-1004(1999)13:3<197::AID-HUMU3>3.0.CO;2-D;
RA Marie S., Cuppens H., Heuterspreute M., Jaspers M., Tola E.Z.,
RA Gu X.X., Legius E., Vincent M.-F., Jaeken J., Cassiman J.-J.,
RA van den Berghe G.;
RT "Mutation analysis in adenylosuccinate lyase deficiency: eight novel
RT mutations in the re-evaluated full ADSL coding sequence.";
RL Hum. Mutat. 13:197-202(1999).
RN [18]
RP CHARACTERIZATION OF VARIANTS ADSL DEFICIENCY VAL-2; LEU-26; TRP-141;
RP CYS-303; ARG-395; HIS-426 AND SER-450.
RX PubMed=10958654; DOI=10.1093/hmg/9.14.2159;
RA Race V., Marie S., Vincent M.-F., Van den Berghe G.;
RT "Clinical, biochemical and molecular genetic correlations in
RT adenylosuccinate lyase deficiency.";
RL Hum. Mol. Genet. 9:2159-2165(2000).
RN [19]
RP VARIANTS ADSL DEFICIENCY VAL-311; MET-364; HIS-396 AND PRO-452.
RX PubMed=12368987; DOI=10.1055/s-2002-34493;
RA Castro M., Perez-Cerda C., Merinero B., Garcia M.J., Bernar J.,
RA Gil Nagel A., Torres J., Bermudez M., Garavito P., Marie S.,
RA Vincent F., Van den Berghe G., Ugarte M.;
RT "Screening for adenylosuccinate lyase deficiency: clinical,
RT biochemical and molecular findings in four patients.";
RL Neuropediatrics 33:186-189(2002).
RN [20]
RP VARIANT ADSL DEFICIENCY HIS-426.
RX PubMed=12833398; DOI=10.1002/ajmg.a.20176;
RA Edery P., Chabrier S., Ceballos-Picot I., Marie S., Vincent M.-F.,
RA Tardieu M.;
RT "Intrafamilial variability in the phenotypic expression of
RT adenylosuccinate lyase deficiency: a report on three patients.";
RL Am. J. Med. Genet. A 120:185-190(2003).
RN [21]
RP CHARACTERIZATION OF VARIANTS ADSL DEFICIENCY CYS-194; GLU-246;
RP VAL-311; CYS-396 AND HIS-396, AND ENZYME REGULATION.
RX PubMed=19405474; DOI=10.1021/bi802321m;
RA Ariyananda Lde Z., Lee P., Antonopoulos C., Colman R.F.;
RT "Biochemical and biophysical analysis of five disease-associated human
RT adenylosuccinate lyase mutants.";
RL Biochemistry 48:5291-5302(2009).
CC -!- FUNCTION: Catalyzes two non-sequential steps in de novo AMP
CC synthesis: converts (S)-2-(5-amino-1-(5-phospho-D-
CC ribosyl)imidazole-4-carboxamido)succinate (SAICAR) to fumarate
CC plus 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide, and
CC thereby also contributes to de novo IMP synthesis, and converts
CC succinyladenosine monophosphate (SAMP) to AMP and fumarate.
CC -!- CATALYTIC ACTIVITY: N(6)-(1,2-dicarboxyethyl)AMP = fumarate + AMP.
CC -!- CATALYTIC ACTIVITY: (S)-2-(5-amino-1-(5-phospho-D-
CC ribosyl)imidazole-4-carboxamido)succinate = fumarate + 5-amino-1-
CC (5-phospho-D-ribosyl)imidazole-4-carboxamide.
CC -!- ENZYME REGULATION: The enzyme reaction kinetics indicate
CC cooperativity between subunits.
CC -!- PATHWAY: Purine metabolism; AMP biosynthesis via de novo pathway;
CC AMP from IMP: step 2/2.
CC -!- PATHWAY: Purine metabolism; IMP biosynthesis via de novo pathway;
CC 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-
CC amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate: step 2/2.
CC -!- SUBUNIT: Homotetramer. Residues from neighboring subunits
CC contribute catalytic and substrate-binding residues to each active
CC site.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P30566-1; Sequence=Displayed;
CC Name=2; Synonyms=Delta-ADSL;
CC IsoId=P30566-2; Sequence=VSP_000318;
CC Note=Lacks enzymatic activity;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Both isoforms are
CC produced by all tissues. Isoform 2 is 10-fold less abundant than
CC isoform 1.
CC -!- DISEASE: Adenylosuccinase deficiency (ADSL deficiency)
CC [MIM:103050]: An autosomal recessive disorder characterized by the
CC accumulation in the body fluids of succinylaminoimidazole-
CC carboxamide riboside (SAICA-riboside) and succinyladenosine (S-
CC Ado). Most children display marked psychomotor delay, often
CC accompanied by epilepsy or autistic features, or both, although
CC some patients may be less profoundly retarded. Occasionally,
CC growth retardation and muscular wasting are also present. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the lyase 1 family. Adenylosuccinate lyase
CC subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC60603.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAA46697.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=ADSLdb; Note=Adenylosuccinate lyase mutations
CC database;
CC URL="http://www.icp.ucl.ac.be/adsldb/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ADSL";
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DR EMBL; X65867; CAA46696.1; -; mRNA.
DR EMBL; X65867; CAA46697.1; ALT_INIT; mRNA.
DR EMBL; AF067853; AAC21560.1; -; mRNA.
DR EMBL; AF067854; AAC21561.1; -; mRNA.
DR EMBL; CR456368; CAG30254.1; -; mRNA.
DR EMBL; AL022238; CAI18983.1; -; Genomic_DNA.
DR EMBL; AL022238; CAQ08930.1; -; Genomic_DNA.
DR EMBL; CH471095; EAW60375.1; -; Genomic_DNA.
DR EMBL; BC000253; AAH00253.1; -; mRNA.
DR EMBL; S60710; AAC60603.1; ALT_INIT; mRNA.
DR RefSeq; NP_000017.1; NM_000026.2.
DR RefSeq; NP_001116850.1; NM_001123378.1.
DR UniGene; Hs.75527; -.
DR PDB; 2J91; X-ray; 1.80 A; A/B/C/D=1-481.
DR PDB; 2VD6; X-ray; 2.00 A; A/B/C/D=1-481.
DR PDB; 4FFX; X-ray; 2.70 A; A/B/C/D=1-484.
DR PDB; 4FLC; X-ray; 2.60 A; A/B/C/D=1-484.
DR PDBsum; 2J91; -.
DR PDBsum; 2VD6; -.
DR PDBsum; 4FFX; -.
DR PDBsum; 4FLC; -.
DR ProteinModelPortal; P30566; -.
DR SMR; P30566; 5-474.
DR IntAct; P30566; 4.
DR STRING; 9606.ENSP00000216194; -.
DR PhosphoSite; P30566; -.
DR DMDM; 6686318; -.
DR PaxDb; P30566; -.
DR PeptideAtlas; P30566; -.
DR PRIDE; P30566; -.
DR DNASU; 158; -.
DR Ensembl; ENST00000216194; ENSP00000216194; ENSG00000239900.
DR Ensembl; ENST00000342312; ENSP00000341429; ENSG00000239900.
DR GeneID; 158; -.
DR KEGG; hsa:158; -.
DR UCSC; uc003ayp.4; human.
DR CTD; 158; -.
DR GeneCards; GC22P040742; -.
DR HGNC; HGNC:291; ADSL.
DR HPA; CAB019285; -.
DR HPA; HPA000525; -.
DR MIM; 103050; phenotype.
DR MIM; 608222; gene.
DR neXtProt; NX_P30566; -.
DR Orphanet; 46; Adenylosuccinate lyase deficiency.
DR PharmGKB; PA24600; -.
DR eggNOG; COG0015; -.
DR HOGENOM; HOG000033915; -.
DR HOVERGEN; HBG000214; -.
DR InParanoid; P30566; -.
DR KO; K01756; -.
DR OrthoDB; EOG7GQXVD; -.
DR PhylomeDB; P30566; -.
DR BioCyc; MetaCyc:HS02059-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00074; UER00132.
DR UniPathway; UPA00075; UER00336.
DR EvolutionaryTrace; P30566; -.
DR GeneWiki; Adenylosuccinate_lyase; -.
DR GenomeRNAi; 158; -.
DR NextBio; 629; -.
DR PRO; PR:P30566; -.
DR ArrayExpress; P30566; -.
DR Bgee; P30566; -.
DR CleanEx; HS_ADSL; -.
DR Genevestigator; P30566; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0070626; F:(S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate AMP-lyase (fumarate-forming) activity; IEA:UniProtKB-EC.
DR GO; GO:0004018; F:N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity; IDA:UniProtKB.
DR GO; GO:0044208; P:'de novo' AMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0006189; P:'de novo' IMP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0009060; P:aerobic respiration; IEA:Ensembl.
DR GO; GO:0006167; P:AMP biosynthetic process; IDA:UniProtKB.
DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB.
DR GO; GO:0006144; P:purine nucleobase metabolic process; TAS:Reactome.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0042594; P:response to starvation; IEA:Ensembl.
DR Gene3D; 1.10.275.10; -; 1.
DR InterPro; IPR019468; AdenyloSucc_lyase_C.
DR InterPro; IPR024083; Fumarase/histidase_N.
DR InterPro; IPR020557; Fumarate_lyase_CS.
DR InterPro; IPR000362; Fumarate_lyase_fam.
DR InterPro; IPR022761; Fumarate_lyase_N.
DR InterPro; IPR008948; L-Aspartase-like.
DR InterPro; IPR004769; Pur_lyase.
DR PANTHER; PTHR11444; PTHR11444; 1.
DR PANTHER; PTHR11444:SF2; PTHR11444:SF2; 1.
DR Pfam; PF10397; ADSL_C; 1.
DR Pfam; PF00206; Lyase_1; 1.
DR PRINTS; PR00149; FUMRATELYASE.
DR SMART; SM00998; ADSL_C; 1.
DR SUPFAM; SSF48557; SSF48557; 1.
DR TIGRFAMs; TIGR00928; purB; 1.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Direct protein sequencing; Disease mutation; Epilepsy; Lyase;
KW Purine biosynthesis; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 484 Adenylosuccinate lyase.
FT /FTId=PRO_0000137892.
FT REGION 20 21 Substrate binding; shared with
FT neighboring subunit.
FT REGION 85 87 Substrate binding.
FT REGION 111 112 Substrate binding.
FT ACT_SITE 159 159 Proton donor/acceptor.
FT ACT_SITE 289 289 Proton donor/acceptor.
FT BINDING 241 241 Substrate.
FT BINDING 303 303 Substrate; shared with neighboring
FT subunit.
FT BINDING 329 329 Substrate.
FT BINDING 334 334 Substrate.
FT BINDING 338 338 Substrate.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 147 147 N6-acetyllysine.
FT MOD_RES 295 295 N6-acetyllysine.
FT VAR_SEQ 398 456 Missing (in isoform 2).
FT /FTId=VSP_000318.
FT VARIANT 2 2 A -> V (in ADSL deficiency; severe;
FT dbSNP:rs143083947).
FT /FTId=VAR_016930.
FT VARIANT 3 3 A -> V (in ADSL deficiency; severe).
FT /FTId=VAR_017078.
FT VARIANT 26 26 M -> L (in ADSL deficiency; severe).
FT /FTId=VAR_016931.
FT VARIANT 31 31 S -> N (in dbSNP:rs5757921).
FT /FTId=VAR_037883.
FT VARIANT 72 72 I -> V (in ADSL deficiency; severe).
FT /FTId=VAR_007972.
FT VARIANT 100 100 P -> A (in ADSL deficiency; moderate).
FT /FTId=VAR_017079.
FT VARIANT 114 114 Y -> H (in ADSL deficiency; severe. Total
FT loss of activity).
FT /FTId=VAR_017080.
FT VARIANT 141 141 R -> W (in ADSL deficiency; severe).
FT /FTId=VAR_007973.
FT VARIANT 147 147 K -> M (in dbSNP:rs11089991).
FT /FTId=VAR_037884.
FT VARIANT 190 190 R -> Q (in ADSL deficiency; moderate;
FT dbSNP:rs28941471).
FT /FTId=VAR_007974.
FT VARIANT 194 194 R -> C (in ADSL deficiency; severe.
FT Reduces protein stability).
FT /FTId=VAR_017081.
FT VARIANT 246 246 K -> E (in ADSL deficiency; moderate.
FT Strongly reduced catalytic activity).
FT /FTId=VAR_007975.
FT VARIANT 268 268 D -> N (in ADSL deficiency; severe. Total
FT loss of activity).
FT /FTId=VAR_017082.
FT VARIANT 303 303 R -> C (in ADSL deficiency; mild.
FT Strongly reduced activity with SAMP, but
FT only slightly reduced activity with
FT SAICAR. Abolishes cooperativity).
FT /FTId=VAR_007976.
FT VARIANT 311 311 L -> V (in ADSL deficiency; severe.
FT Slightly reduced enzyme activity).
FT /FTId=VAR_017083.
FT VARIANT 318 318 P -> L (in ADSL deficiency; severe).
FT /FTId=VAR_017084.
FT VARIANT 364 364 V -> M (in ADSL deficiency; severe).
FT /FTId=VAR_017085.
FT VARIANT 374 374 R -> W (in ADSL deficiency; severe).
FT /FTId=VAR_017086.
FT VARIANT 395 395 S -> R (in ADSL deficiency; severe).
FT /FTId=VAR_007977.
FT VARIANT 396 396 R -> C (in ADSL deficiency; severe.
FT Abolishes cooperativity and reduces
FT enzyme activity).
FT /FTId=VAR_017087.
FT VARIANT 396 396 R -> H (in ADSL deficiency; severe.
FT Abolishes cooperativity and reduces
FT enzyme activity).
FT /FTId=VAR_017088.
FT VARIANT 422 422 D -> Y (in ADSL deficiency; moderate).
FT /FTId=VAR_017089.
FT VARIANT 423 423 L -> V (in ADSL deficiency; moderate).
FT /FTId=VAR_017090.
FT VARIANT 426 426 R -> H (in ADSL deficiency; severe. Most
FT frequent mutation).
FT /FTId=VAR_007978.
FT VARIANT 430 430 D -> N (in ADSL deficiency; mild).
FT /FTId=VAR_017091.
FT VARIANT 438 438 S -> P (in ADSL deficiency; severe).
FT /FTId=VAR_000680.
FT VARIANT 447 447 S -> P (in ADSL deficiency; severe).
FT /FTId=VAR_017092.
FT VARIANT 450 450 T -> S (in ADSL deficiency; moderate).
FT /FTId=VAR_016932.
FT VARIANT 452 452 R -> P (in ADSL deficiency; severe).
FT /FTId=VAR_017093.
FT HELIX 16 19
FT HELIX 24 29
FT HELIX 32 53
FT HELIX 59 66
FT STRAND 68 70
FT HELIX 74 84
FT HELIX 87 98
FT TURN 100 102
FT HELIX 103 105
FT TURN 106 109
FT HELIX 113 148
FT TURN 149 151
FT STRAND 153 158
FT STRAND 161 167
FT HELIX 168 192
FT STRAND 201 204
FT HELIX 206 211
FT TURN 212 214
FT HELIX 216 229
FT STRAND 240 242
FT HELIX 246 274
FT STRAND 277 279
FT HELIX 299 313
FT HELIX 316 323
FT HELIX 331 333
FT HELIX 334 360
FT HELIX 366 380
FT HELIX 382 389
FT HELIX 396 416
FT HELIX 423 429
FT HELIX 431 433
FT HELIX 434 437
FT HELIX 440 443
FT HELIX 446 449
FT HELIX 453 463
FT HELIX 465 469
FT HELIX 470 472
SQ SEQUENCE 484 AA; 54889 MW; 7AA3A0A2C681FD94 CRC64;
MAAGGDHGSP DSYRSPLASR YASPEMCFVF SDRYKFRTWR QLWLWLAEAE QTLGLPITDE
QIQEMKSNLE NIDFKMAAEE EKRLRHDVMA HVHTFGHCCP KAAGIIHLGA TSCYVGDNTD
LIILRNALDL LLPKLARVIS RLADFAKERA SLPTLGFTHF QPAQLTTVGK RCCLWIQDLC
MDLQNLKRVR DDLRFRGVKG TTGTQASFLQ LFEGDDHKVE QLDKMVTEKA GFKRAFIITG
QTYTRKVDIE VLSVLASLGA SVHKICTDIR LLANLKEMEE PFEKQQIGSS AMPYKRNPMR
SERCCSLARH LMTLVMDPLQ TASVQWFERT LDDSANRRIC LAEAFLTADT ILNTLQNISE
GLVVYPKVIE RRIRQELPFM ATENIIMAMV KAGGSRQDCH EKIRVLSQQA ASVVKQEGGD
NDLIERIQVD AYFSPIHSQL DHLLDPSSFT GRASQQVQRF LEEEVYPLLK PYESVMKVKA
ELCL
//

MIM 103050
*RECORD*
*FIELD* NO
103050
*FIELD* TI
#103050 ADENYLOSUCCINASE DEFICIENCY
;;ADENYLOSUCCINATE LYASE DEFICIENCY;;
ADSL DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because adenylosuccinase
deficiency is caused by mutation in the gene encoding adenylosuccinate
lyase (ADSL; 608222).

CLINICAL FEATURES

In 3 children with severe psychomotor delay and autism, Jaeken and Van
den Berghe (1984) found succinyladenosine and succinylaminoimidazole
carboxamide (SAICA) ribotide in the body fluids. Concentrations of both
compounds were about 100 micromol/l in CSF, between 5 and 10 micromol/l
in plasma, and in the millimol/l range in urine. Normally these
compounds are not found in blood and CSF but may be detected in trace
amounts in urine. The authors noted that the compounds are
dephosphorylated derivatives of the intracellular metabolites
adenylosuccinate and succinylaminoimidazole carboxamide ribotide, the 2
substrates of adenylosuccinase (adenylosuccinate lyase). Assays of the
enzyme in 1 patient showed marked reduction of activity in liver and
absence of activity in the kidney. Two of the 3 affected children were
brother and sister, offspring of related Moroccan parents. The authors
suggested that adenylosuccinase deficiency is a specific autosomal
recessive cause of autism.

Jaeken et al. (1988) presented clinical and biochemical data on 8
children with adenylosuccinase deficiency. Seven of the 8 children
showed severe psychomotor retardation. Epilepsy was documented in 5,
autistic features in 3, and growth retardation associated with muscular
wasting in a brother and sister. One female patient was strikingly less
retarded mentally and had only mild psychomotor retardation. In this
patient, the ratio of the 2 metabolites in body fluids was quite
different from that in the severely retarded patients, showing an
approximately 5-fold excess of succinyladenosine. In addition,
adenylosuccinase activity in fibroblasts was only about 6% of normal,
whereas it was about 40% of normal in 6 severely retarded patients. At
least 2 of the patients from separate families were the offspring of
consanguineous parents. Jaeken et al. (1992) described a patient with an
intermediate phenotypic severity resulting from adenylosuccinase
deficiency. Chemical findings in the patient supported the impression
that there is an inverse relationship between the degree of clinical
involvement and the excess of succinyladenosine over SAICA riboside.
Jaeken et al. (1992) concluded that SAICA riboside may be the offending
compound that interferes with neurofunction and that succinyladenosine
may protect against its effects.

In Prague, Sebesta et al. (1997) screened urine samples from more than
2,000 children with unexplained neurologic disease. Using thin-layer
chromatography, they identified 2 boys and 3 girls in 4 kindreds with
adenylosuccinase deficiency. Two of the 4 kindreds were of Gypsy origin.
Two boys were diagnosed at ages 2 and 5 years and 3 girls were diagnosed
at ages 9 months, 3 years, and 6 years. The onset of the disease ranged
from the fourteenth day to 6 months. Two sibs exhibited a less severe
clinical picture and identical clinical course. They came to attention
at the first year of life when psychomotor retardation developed.
Neurologic examination showed hypotonia and hyperactivity. All 3 of the
other patients exhibited severe psychomotor retardation in early
infancy.

Whereas most cases of adenylosuccinase deficiency had been detected by
metabolic screening for severe psychomotor retardation, Maaswinkel-Mooij
et al. (1997) described an infant who manifested generalized seizures as
a first symptom of the disorder. She was initially diagnosed with West
syndrome (308350). The first admission was at 9 weeks of age. The
patient was treated with phenobarbital and remained seizure-free for 10
months. At the age of 15 months, she was reinvestigated because of a
cluster of tonic seizures, and electroencephalogram showed
hypsarrhythmia. Psychomotor retardation became apparent in the second
year of life.

Holder-Espinasse et al. (2002) reported 2 patients with adenylosuccinase
deficiency who had similar mild facial dysmorphic features including
brachycephaly, prominent metopic sutures, a small nose with anteverted
nostrils, long and smooth philtrum, thin upper lip, and low-set ears.
They noted that a patient previously reported by Nassogne et al. (2000)
had similar features.

- Clinical Variability

Edery et al. (2003) observed an unusually variable combination of
clinical features and striking intrafamilial variability in the
phenotype. Among 3 sibs from a family originally from Portugal, the
proband had marked psychomotor regression and progressive cerebellar
vermis atrophy; the other 2 affected sibs presented mainly autistic
features. The sibs were homozygous for the R426H mutation (608222.0002).
The authors suggested that, in any patient with mental retardation of
unexplained origin, adenylosuccinate lyase deficiency should be
considered and assessed using a simple urinary screening method for the
presence of succinylpurines.

Gitiaux et al. (2009) reported 2 sisters, ages 11 and 12 years, with
genetically confirmed adenylosuccinate lyase deficiency (608222.0008).
The girls presented with global developmental delay, motor apraxia,
severe speech deficits, and seizures. They also had unusual behavioral
features, including excessive laughter, very happy disposition,
hyperactivity, short attention span, mouthing of objects, tantrums, and
stereotyped movements, which were reminiscent of Angelman syndrome (AS;
105830). Both had had an increased succinyladenosine/SAICAr ratio of
1.6. Gitiaux et al. (2009) postulated that this may be a new clinical
presentation of adenylosuccinate lyase deficiency.

BIOCHEMICAL FEATURES

The de novo purine biosynthesis pathway involves 10 steps that lead from
5-phosphoribosylpyrophosphate (PRPP) to inosine monophosphate (IMP),
from which the adenine and guanine nucleotides are formed. Marie et al.
(2004) noted that deficiency of adenylosuccinate lyase (ADSL) was the
first inborn deficiency of purine synthesis to be identified in humans.
This disorder is characterized by the presence in urine and
cerebrospinal fluid of succinyl-5-amino-4-imidazolecarboxamide riboside
(SAICA-riboside) and succinyladenosine (S-Ado), the nucleosides
corresponding to SAICA-ribotide (SARCAR) and adenylosuccinate (S-AMP),
respectively, the 2 substrates of ADSL.

In patients with ADSL deficiency, the lower the S-Ado:SAICAr ratio in
CSF, the more severe the phenotype. Patients with neonatal fatal disease
have a ratio less than 1, those who present in the first months of life
with a severe form of the disorder have a ratio of about 1, whereas
those who present later with a relatively milder phenotype have ratios
equal to or greater than 2 (Jurecka et al., 2008).

DIAGNOSIS

Maddocks and Reed (1989) described a sensitive and specific test for
succinyladenosine in the urine.

Jaeken et al. (1992) suggested that a modified Bratton-Marshall test,
originally designed as an assay for sulfonamides, would be a practical
screening method for the disorder, provided the patients are not
receiving sulfonamides.

MOLECULAR GENETICS

In 2 affected Moroccan sibs reported by Jaeken and Van den Berghe
(1984), Stone et al. (1992) identified a point mutation in the ADSL gene
(608222.0001).

Marie et al. (1999) found reports of 9 missense mutations in the ADSL
gene in 6 apparently unrelated sibships. In a study of 10 additional
patients with ADSL deficiency, they found 9 point mutations.

Kmoch et al. (2000) identified 8 mutations among 6 ADSL patients.
Expression studies of the mutant proteins showed that the level of
residual enzyme activity correlated with the severity of the clinical
phenotype.

Among 7 unrelated Polish patients with ADSL deficiency, Jurecka et al.
(2008) identified 7 biallelic mutations in the ADSL gene, including 5
novel mutations. R426H (608222.0002) was the most common mutation. One
patient had a fatal neonatal course, 4 had a severe phenotype with
intractable seizures and psychomotor retardation since early infancy,
and 2 had a milder phenotype with later-onset, transient visual contact
disturbance, and mild to moderate psychomotor retardation. There was no
apparent genotype/phenotype correlation.

*FIELD* RF
1. Edery, P.; Chabrier, S.; Ceballos-Picot, I.; Marie, S.; Vincent,
M.-F.; Tardieu, M.: Intrafamilial variability in the phenotypic expression
of adenylosuccinate lyase deficiency: a report on three patients. Am.
J. Med. Genet. 120A: 185-190, 2003.

2. Gitiaux, C.; Ceballos-Picot, I.; Marie, S.; Valayannopoulos, V.;
Rio, M.; Verrieres, S.; Benoist, J. F.; Vincent, M. F.; Desguerre,
I.; Bahi-Buisson, N.: Misleading behavioural phenotype with adenylosuccinate
lyase deficiency. Europ. J. Hum. Genet. 17: 133-136, 2009.

3. Holder-Espinasse, M.; Marie, S.; Bourrouillou, G.; Ceballos-Picot,
I.; Nassogne, M.-C.; Faivre, L.; Amiel, J.; Munnich, A.; Vincent,
M.-F.; Cormier-Daire, V.: Towards a suggestive facial dysmorphism
in adenylosuccinate lyase deficiency? (Letter) J. Med. Genet. 39:
440-442, 2002.

4. Jaeken, J.; Van den Bergh, F.; Vincent, M. F.; Casaer, P.; Van
den Berghe, G.: Adenylosuccinase deficiency: a newly recognized variant. J.
Inherit. Metab. Dis. 15: 416-418, 1992.

5. Jaeken, J.; Van den Berghe, G.: An infantile autistic syndrome
characterised by the presence of succinylpurines in body fluids. Lancet 324:
1058-1061, 1984. Note: Originally Volume II.

6. Jaeken, J.; Wadman, S. K.; Duran, M.; van Sprang, F. J.; Beemer,
F. A.; Holl, R. A.; Theunissen, P. M.; de Cock, P.; van den Bergh,
F.; Vincent, M. F.; van den Berghe, G.: Adenylosuccinase deficiency:
an inborn error of purine nucleotide synthesis. Europ. J. Pediat. 148:
126-131, 1988.

7. Jurecka, A.; Zikanova, M.; Tylki-Szymanska, A.; Krijt, J.; Bogdanska,
A.; Gradowska, W.; Mullerova, K.; Sykut-Cegielska, J.; Kmoch, S.;
Pronicka, E.: Clinical, biochemical and molecular findings in seven
Polish patients with adenylosuccinate lyase deficiency. Molec. Genet.
Metab. 94: 435-442, 2008.

8. Kmoch, S.; Hartmannova, H.; Stiburkova, B.; Krijt, J.; Zikanova,
M.; Sebesta, I.: Human adenylosuccinate lyase (ADSL), cloning and
characterization of full-length cDNA and its isoform, gene structure
and molecular basis for ADSL deficiency in six patients. Hum. Molec.
Genet. 9: 1501-1513, 2000.

9. Maaswinkel-Mooij, P. D.; Laan, L. A. E. M.; Onkenhout, W.; Brouwer,
O. F.; Jaeken, J.; Poorthuis, B. J. H. M.: Adenylosuccinase deficiency
presenting with epilepsy in early infancy. J. Inherit. Metab. Dis. 20:
606-607, 1997.

10. Maddocks, J.; Reed, T.: Urine test for adenylosuccinase deficiency
in autistic children. (Letter) Lancet 339: 158-159, 1989. Note:
Originally Volume I.

11. Marie, S.; Cuppens, H.; Heuterspreute, M.; Jaspers, M.; Tola,
E. Z.; Gu, X. X.; Legius, E.; Vincent, M.-F.; Jaeken, J.; Cassiman,
J.-J.; Van den Berghe, G.: Mutation analysis in adenylosuccinate
lyase deficiency: eight novel mutations in the re-evaluated full ADSL
coding sequence. Hum. Mutat. 13: 197-202, 1999.

12. Marie, S.; Heron, B.; Bitoun, P.; Timmerman, T.; Van den Berghe,
G.; Vincent, M.-F.: AICA-ribosiduria: a novel, neurologically devastating
inborn error of purine biosynthesis caused by mutation of ATIC. Am.
J. Hum. Genet. 74: 1276-1281, 2004.

13. Nassogne, M.-C.; Henrot, B.; Aubert, G.; Bonnier, C.; Marie, S.;
Saint-Martin, C.; Van den Berghe, G.; Sebire, G.; Vincent, M.-F.:
Adenylsuccinase deficiency: an unusual cause of early-onset epilepsy
associated with acquired microcephaly. Brain Dev. 22: 383-386, 2000.

14. Sebesta, I.; Krijt, J.; Kmoch, S.; Hartmannova, H.; Wojda, M.;
Zeman, J.: Adenylosuccinase deficiency: clinical and biochemical
findings in 5 Czech patients. J. Inherit. Metab. Dis. 20: 343-344,
1997.

15. Stone, R. L.; Aimi, J.; Barshop, B. A.; Jaeken, J.; Van den Berghe,
G.; Zalkin, H.; Dixon, J. E.: A mutation in adenylosuccinate lyase
associated with mental retardation and autistic features. Nature
Genet. 1: 59-63, 1992.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Growth retardation

HEAD AND NECK:
[Head];
Brachycephaly;
Microcephaly (less common);
Prominent metopic suture;
[Face];
Long smooth philtrum;
[Ears];
Low-set ears;
[Eyes];
Strabismus;
Nystagmus;
[Nose];
Small nose;
Anteverted nostrils;
[Mouth];
Thin upper lip;
Wide mouth

MUSCLE, SOFT TISSUE:
Muscle wasting

NEUROLOGIC:
[Central nervous system];
Psychomotor delay, severe;
Mental retardation;
Hypotonia;
Gait ataxia;
Inability to walk;
Poor eye contact;
Poor language and speech development;
Seizures, refractory;
Spasticity;
Opisthotonus;
Myoclonus;
Brisk reflexes;
Cerebral atrophy;
Cerebellar atrophy;
Hypomyelination;
[Behavioral/psychiatric manifestations];
Autistic features;
Hyperactivity;
Aggressive behavior;
Temper tantrums;
Stereotypic movements;
Self-mutilation;
Happy demeanor (reported in 1 family);
Inappropriate laughter (reported in 1 family)

LABORATORY ABNORMALITIES:
Increased succinyladenosine (S-Ado) in serum, urine, and CSF;
Increased succinylaminoimidazole carboxamide ribotide (SAICAr);
Decreased S-Ado:SAICAr ratio;
Adenylosuccinase deficiency

MISCELLANEOUS:
Onset in infancy;
Highly variable phenotype, ranging from neonatal encephalopathy to
mild mental retardation with autistic features;
The lower the S-Ado:SAICr ratio, the more severe the phenotype

MOLECULAR BASIS:
Caused by mutation in the adenylosuccinate lyase gene (ADSL, 608222.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 4/3/2009

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 02/22/2011
joanna: 10/27/2009
ckniffin: 4/9/2009
ckniffin: 4/3/2009
alopez: 1/19/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 4/3/2009
Victor A. McKusick - updated: 1/19/2005
Anne M. Stumpf - updated: 5/25/2004
Cassandra L. Kniffin - reorganized: 11/6/2003
Cassandra L. Kniffin - updated: 11/3/2003
Victor A. McKusick - updated: 7/17/2002
George E. Tiller - updated: 10/17/2000
Victor A. McKusick - updated: 3/12/1999
Victor A. McKusick - updated: 11/11/1998
Victor A. McKusick - updated: 2/12/1998

*FIELD* CD
Victor A. McKusick: 12/15/1986

*FIELD* ED
wwang: 04/17/2009
ckniffin: 4/9/2009
ckniffin: 4/3/2009
wwang: 2/10/2009
terry: 1/7/2009
wwang: 1/19/2005
alopez: 5/25/2004
terry: 2/20/2004
carol: 11/6/2003
ckniffin: 11/3/2003
tkritzer: 7/29/2002
terry: 7/17/2002
cwells: 2/21/2001
mcapotos: 11/30/2000
alopez: 10/17/2000
carol: 3/15/1999
terry: 3/12/1999
carol: 11/11/1998
mark: 2/18/1998
terry: 2/12/1998
alopez: 6/3/1997
terry: 2/11/1997
mark: 8/25/1995
mimadm: 3/11/1994
carol: 11/3/1993
carol: 3/25/1993
carol: 11/5/1992
carol: 9/29/1992

MIM 608222
*RECORD*
*FIELD* NO
608222
*FIELD* TI
*608222 ADENYLOSUCCINATE LYASE; ADSL
;;ADENYLOSUCCINASE
*FIELD* TX

DESCRIPTION

Adenylosuccinate lyase (adenylosuccinase, ADSL; EC 4.3.2.2) is an enzyme
read moreinvolved in 2 pathways of purine nucleotide metabolism. It catalyzes
cleavage of succinyl groups to yield fumarate: the conversion of
succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole
carboxamide ribotide (AICAR) along the de novo pathway, and the
formation of adenylate (AMP) from adenylosuccinate (S-AMP) in the
conversion of inosine monophosphate (IMP) into adenine nucleotides in
the purine nucleotide cycle (summary by Jurecka et al., 2008).

CLONING

Using an avian liver ADSL cDNA as a probe to screen a human liver cDNA
library, Stone et al. (1992) isolated an ADSL cDNA encoding a 459-amino
acid protein with a molecular mass of 52 kD. The enzyme has a
homotetrameric structure.

Marie et al. (1999) found that the human ADSL cDNA contains an
additional segment at the 5-prime end, encoding a protein of 484 amino
acids, rather than 459 as previously reported. Kmoch et al. (2000)
reported the complete human ADSL cDNA sequence, which revealed the novel
52-bp sequence at the 5-prime end of the ADSL gene, containing an
alternate initiation codon. This longer sequence was termed 'M1,' and
the shorter one 'M2.' Expression studies showed that the M1 protein was
soluble, active, and stable, in contrast to M2, which was insoluble and
inactive. The authors noted that the native human protein is composed of
484 amino acids, the same as murine ADSL. In addition, Kmoch et al.
(2000) found 2 ADSL isoforms produced by alternative splicing of exon
12. Both transcripts were expressed in all tissues studied, with the
unspliced form being about 10-fold more abundant. The authors
hypothesized that the inactive isoform may be able to form tetramers
with the active isoform, forming an array of enzymes with different
activities depending on the composition of the tetramer.

Wong and O'Brien (1995) cloned the mouse ADSL gene, and found that the
human and mouse ADSL proteins share 94% identity.

GENE STRUCTURE

Kmoch et al. (2000) determined that the human ADSL gene contains 13
exons.

Wong and O'Brien (1995) determined that the murine ADSL gene contains 13
exons. Comparison of the exon/intron structure of this gene with the
argininosuccinate lyase gene (ASL; 608310) did not suggest gene
duplication or exon shuffling as a mechanism of evolution in the
fumarate gene family.

MAPPING

To map the human gene responsible for adenylosuccinase deficiency
(103050), Van Keuren et al. (1986, 1987) used somatic cell hybridization
of human cells with Chinese hamster ovary (CHO-K1) mutants, designated
ade(-)I, deficient in specific steps of the purine biosynthesis pathway.
As ade(-)I cells require exogenous adenine for growth, cell hybrids were
selected for purine prototrophy in adenine-free medium. Human chromosome
22 was found to be required for growth without adenine. Assignment of
the gene for adenylosuccinase to chromosome 22 was confirmed by Southern
blot analysis with a DNA probe that had been isolated from a human fetal
brain library and previously mapped to chromosome 22. By Southern
blotting techniques using somatic cell hybrids, Budarf et al. (1991)
demonstrated that ADSL maps to 22q13.1, distal to the Ewing sarcoma
breakpoint (133450). Using both a somatic cell hybrid mapping panel and
fluorescence in situ hybridization, Fon et al. (1993) localized the ADSL
gene to 22q13.1-q13.2.

GENE FUNCTION

Adenylosuccinase carries out two independent but similar steps of purine
biosynthesis: the removal of a fumarate from succinylaminoimidazole
carboxamide (SAICA) ribotide to give aminoimidazole carboxamide
ribotide, and removal of fumarate from adenylosuccinate to give AMP.
These are the ninth and the thirteenth steps of adenylate biosynthesis
(Van Keuren et al., 1986, 1987).

MOLECULAR GENETICS

In 2 Moroccan sibs with adenylosuccinase deficiency (103050) reported by
Jaeken and Van den Berghe (1984), Stone et al. (1992) identified a point
mutation in the ADSL gene (608222.0001).

In an infant with adenylosuccinase deficiency, Maaswinkel-Mooij et al.
(1997) reported homozygosity for an arg401-to-his (R401H) mutation
(608222.0002) in the ADSL gene; this mutation was later designated
arg426-to-his (R426H) based on the finding of Marie et al. (1999) that
human ADSL encodes a protein of 484 rather than 459 amino acids. Marie
et al. (1999) found reports of 9 missense mutations in the ADSL gene in
6 apparently unrelated sibships with ADSL deficiency. In a study of 10
additional affected patients, they found 9 point mutations, among which
7 were previously unreported missense mutations and 1 was the first
splicing error reported in this disorder. With the exception of 3
mutations, R426H, which was found in 5 apparently unrelated patients,
R190Q (608222.0005), which had previously been reported, and K246E
(608222.0006), which was found in 2 unrelated patients, all other
mutations were found only in a single family.

Among 6 patients with ADSL deficiency, Kmoch et al. (2000) identified 8
mutations in the ADSL gene. Expression studies of the mutant proteins
showed that the level of residual enzyme activity correlated with the
severity of the clinical phenotype. However, all patients had at least 1
allele with residual ADSL activity, suggesting that complete loss of
activity is not compatible with life.

Among 7 unrelated Polish patients with ADSL deficiency, Jurecka et al.
(2008) identified 7 biallelic mutations in the ADSL gene, including 5
novel mutations. R426H (608222.0002) was the most common mutation. One
patient had a fatal neonatal course, 4 had a severe phenotype with
intractable seizures and psychomotor retardation since early infancy,
and 2 had a milder phenotype with later-onset, transient visual contact
disturbance, and mild to moderate psychomotor retardation. There was no
apparent genotype/phenotype correlation.

*FIELD* AV
.0001
ADENYLOSUCCINASE DEFICIENCY
ADSL, SER413PRO

In 2 Moroccan sibs with adenylosuccinase deficiency (103050) originally
reported by Jaeken and Van den Berghe (1984), Stone et al. (1992)
identified a mutation in the ADSL gene, resulting in a ser413-to-pro
(S413P) substitution that led to structural instability of the mutant
enzyme.

.0002
ADENYLOSUCCINASE DEFICIENCY
ADSL, ARG426HIS

In an infant in which epilepsy was the first manifestation of
adenylosuccinase deficiency (103050). Maaswinkel-Mooij et al. (1997)
reported homozygosity for an arg401-to-his (R401H) substitution in the
ADSL gene.

Marie et al. (1999) found 5 apparently unrelated patients with
adenylosuccinate lyase deficiency who had an arg426-to-his (R426H)
mutation, which had previously been identified as R401H by
Maaswinkel-Mooij et al. (1997). The discrepancy in the numbering system
was due to the finding by Marie et al. (1999) that the cDNA of human
ADSL encodes a protein of 484 rather than 459 amino acids. The authors
noted that 426H mutation was the most frequent one identified up to that
time, accounting for 12 of the 34 alleles investigated.

Kmoch et al. (2000) described an additional patient homozygous for the
R426H mutation.

Edery et al. (2003) observed an unusually variable combination of
clinical features and striking intrafamilial variability in the
phenotype. Among 3 sibs from a family originally from Portugal, the
proband had marked psychomotor regression and progressive cerebellar
vermis atrophy; the other 2 affected sibs presented mainly autistic
features. The sibs were homozygous for the R426H mutation. The authors
suggested that, in any patient with mental retardation of unexplained
origin, adenylosuccinate lyase deficiency should be considered and
assessed using a simple urinary screening method for the presence of
succinylpurines.

Jurecka et al. (2008) identified homozygosity for the R426H mutation in
2 unrelated Polish patients with ADSL deficiency. One had a severe form
of the disorder with severe psychomotor retardation, inability to walk,
and refractory seizures, and was bedridden by age 9.5. The other had a
relatively less severe phenotype and could sit and walk a few steps at
age 4.5 years. Two additional unrelated Polish patients were compound
heterozygous for the R426H allele and another pathogenic mutation in the
ADSL gene.

.0003
ADENYLOSUCCINASE DEFICIENCY
ADSL, PRO75ALA

In a 13-year-old female who showed a reduced ADSL enzymatic activity in
lymphocytes and red blood cells, and suffered from severe psychomotor
retardation (103050), Verginelli et al. (1998) found compound
heterozygosity for 2 missense mutations in the ADSL gene: a 300C-G
transversion, resulting in a pro75-to-ala (P75A) substitution, and a
1266G-T transversion, resulting in an asp397-to-tyr (D397Y)
substitution. The patient had previously been described by Salerno et
al. (1995, 1997). A few months after birth, motor restlessness,
hypertonicity, and frequent crying attacks were noticed. Eye contact was
difficult, and reaction to auditory stimuli was exaggerated. At age 9
months, absence attacks were noticed. At the age of 5 years, generalized
convulsions were observed for the first time. Growth, including head
circumference, muscle tone and reflexes were normal; gait was awkward.

.0004
ADENYLOSUCCINASE DEFICIENCY
ADSL, ASP397TYR

See 608222.0003 and Verginelli et al. (1998).

.0005
ADENYLOSUCCINASE DEFICIENCY
ADSL, ARG190GLN

In a Belgian patient with adenylosuccinate lyase deficiency (103050),
Marie et al. (1999) identified a 571G-A transition in the ADSL gene,
predicted to result in an arg190-to-gln (R190Q) amino acid substitution.
The mutation was present in compound heterozygous state with a 738A-G
(lys246-to-glu; K246E) mutation in the other allele (608222.0006). This
mutation had been reported in heterozygous state in 2 Czech sibs by
Kmoch et al. (1997).

.0006
ADENYLOSUCCINASE DEFICIENCY
ADSL, LYS246GLU

Marie et al. (1999) found a lys246-to-glu (K246E) mutation in compound
heterozygous state in 2 apparently unrelated Belgian patients with
adenylosuccinate lyase deficiency (103050). See also 608222.0005.

.0007
ADENYLOSUCCINASE DEFICIENCY
ADSL, -49T-C

In 3 unrelated patients with ADSL deficiency (103050), Marie et al.
(2002) identified a -49T-C mutation in the 5-prime untranslated region
of the ADSL allele that displayed a normal coding sequence. Measurements
of the amount of mRNA transcribed from the allele with the promoter
mutation showed that it was reduced to approximately 33% of that
transcribed from the alleles mutated in their coding sequence. Further
investigations showed that the -49T-C mutation provoked a reduction to
25% of wildtype control of promoter function, as evaluated by luciferase
activity and mRNA level in transfection experiments. The mutation also
affected the binding of nuclear respiratory factor-2 (NRF2; 600609), a
known activator of transcription, as assessed by gel-shift studies. The
findings in 3 unrelated patients indicated that a mutation of a
regulatory region of the ADSL gene may be an unusually frequent cause of
ADSL deficiency, and suggested a role for NRF2 in the gene regulation of
the purine of the biosynthetic pathway.

.0008
ADENYLOSUCCINASE DEFICIENCY
ADSL, MET225THR

In 2 sisters, born of consanguineous Moroccan parents, with ADSL
deficiency (103050), Gitiaux et al. (2009) identified a homozygous
674T-C transition in exon 6 of the ADSL gene, resulting in a
met225-to-thr (M225T) substitution. Both girls had an increased
succinyladenosine/SAICAr ratio of 1.6. The sisters, ages 11 and 12
years, presented with global developmental delay, motor apraxia, severe
speech deficits, and seizures. They also had unusual behavioral
features, including excessive laughter, very happy disposition,
hyperactivity, short attention span, mouthing of objects, tantrums, and
stereotyped movements, which were reminiscent of Angelman syndrome
(105830).

*FIELD* RF
1. Budarf, M. L.; Emanuel, B. S.; Collins, J.; Fibison, W.; Barshop,
B. A.: Isolation and regional localization of the human adenylosuccinate
lyase gene. (Abstract) Cytogenet. Cell Genet. 58: 2046 only, 1991.

2. Edery, P.; Chabrier, S.; Ceballos-Picot, I.; Marie, S.; Vincent,
M.-F.; Tardieu, M.: Intrafamilial variability in the phenotypic expression
of adenylosuccinate lyase deficiency: a report on three patients. Am.
J. Med. Genet. 120A: 185-190, 2003.

3. Fon, E. A.; Demczuk, S.; Delattre, O.; Thomas, G.; Rouleau, G.
A.: Mapping of the human adenylosuccinate lyase (ADSL) gene to chromosome
22q13.1-q13.2. Cytogenet. Cell Genet. 64: 201-203, 1993.

4. Gitiaux, C.; Ceballos-Picot, I.; Marie, S.; Valayannopoulos, V.;
Rio, M.; Verrieres, S.; Benoist, J. F.; Vincent, M. F.; Desguerre,
I.; Bahi-Buisson, N.: Misleading behavioural phenotype with adenylosuccinate
lyase deficiency. Europ. J. Hum. Genet. 17: 133-136, 2009.

5. Jaeken, J.; Van den Berghe, G.: An infantile autistic syndrome
characterised by the presence of succinylpurines in body fluids. Lancet 324:
1058-1061, 1984. Note: Originally Volume II.

6. Jurecka, A.; Zikanova, M.; Tylki-Szymanska, A.; Krijt, J.; Bogdanska,
A.; Gradowska, W.; Mullerova, K.; Sykut-Cegielska, J.; Kmoch, S.;
Pronicka, E.: Clinical, biochemical and molecular findings in seven
Polish patients with adenylosuccinate lyase deficiency. Molec. Genet.
Metab. 94: 435-442, 2008.

7. Kmoch, S.; Hartmannova, H.; Krijt, J.; Valik, D.; Jones, J. D.;
Sebesta, L.: Genetic heterogeneity in adenylosuccinate lyase deficiency. Clin.
Biochem. 30: 264 only, 1997.

8. Kmoch, S.; Hartmannova, H.; Stiburkova, B.; Krijt, J.; Zikanova,
M.; Sebesta, I.: Human adenylosuccinate lyase (ADSL), cloning and
characterization of full-length cDNA and its isoform, gene structure
and molecular basis for ADSL deficiency in six patients. Hum. Molec.
Genet. 9: 1501-1513, 2000.

9. Maaswinkel-Mooij, P. D.; Laan, L. A. E. M.; Onkenhout, W.; Brouwer,
O. F.; Jaeken, J.; Poorthuis, B. J. H. M.: Adenylosuccinase deficiency
presenting with epilepsy in early infancy. J. Inherit. Metab. 20:
606-607, 1997.

10. Marie, S.; Cuppens, H.; Heuterspreute, M.; Jaspers, M.; Tola,
E. Z.; Gu, X. X.; Legius, E.; Vincent, M.-F.; Jaeken, J.; Cassiman,
J.-J.; Van den Berghe, G.: Mutation analysis in adenylosuccinate
lyase deficiency: eight novel mutations in the re-evaluated full ADSL
coding sequence. Hum. Mutat. 13: 197-202, 1999.

11. Marie, S.; Race, V.; Nassogne, M.-C.; Vincent, M.-F.; Van den
Berghe, G.: Mutation of a nuclear respiratory factor 2 binding site
in the 5-prime untranslated region of the ADSL gene in three patients
with adenylosuccinate lyase deficiency. Am. J. Hum. Genet. 71: 14-21,
2002.

12. Salerno, C.; Crifo, C.; Giardini, O.: Adenylosuccinase deficiency:
a patient with impaired erythrocyte activity and anomalous response
to intravenous fructose. J. Inherit. Metab. Dis. 18: 602-608, 1995.

13. Salerno, C.; Iotti, S.; Lodi, R.; Crifo, C.; Barbiroli, B.: Failure
of muscle energy metabolism in a patient with adenylosuccinate lyase
deficiency: an in vivo study by phosphorus NMR spectroscopy. Biochim.
Biophys. Acta 1360: 271-276, 1997.

14. Stone, R. L.; Aimi, J.; Barshop, B. A.; Jaeken, J.; Van den Berghe,
G.; Zalkin, H.; Dixon, J. E.: A mutation in adenylosuccinate lyase
associated with mental retardation and autistic features. Nature
Genet. 1: 59-63, 1992.

15. Van Keuren, M. L.; Hart, I.; Kao, F.-T.; Neve, R. L.; Bruns, G.
A. P.; Kurnit, D. M.; Patterson, D.: Human chromosome 22 corrects
the defect in the CHO mutant (Ade-I) lacking adenylosuccinase activity.
(Abstract) Am. J. Hum. Genet. 39: A172 only, 1986.

16. Van Keuren, M. L.; Hart, I. M.; Kao, F.-T.; Neve, R. L.; Bruns,
G. A. P.; Kurnit, D. M.; Patterson, D.: A somatic cell hybrid with
a single human chromosome 22 corrects the defect in the CHO mutant
(Ade-I) lacking adenylosuccinase activity. Cytogenet. Cell Genet. 44:
142-147, 1987.

17. Verginelli, D.; Luckow, B.; Crifo, C.; Salerno, C.; Gross, M.
: Identification of new mutations in the adenylosuccinate lyase gene
associated with impaired enzyme activity in lymphocytes and red blood
cells. Biochim. Biophys. Acta 1406: 81-84, 1998.

18. Wong, L.-J. C.; O'Brien, W. E.: Characterization of the cDNA
and the gene encoding murine adenylosuccinate lyase. Genomics 28:
341-343, 1995.

*FIELD* CN
Cassandra L. Kniffin - updated: 4/3/2009
Victor A. McKusick - updated: 1/12/2005

*FIELD* CD
Cassandra L. Kniffin: 10/31/2003

*FIELD* ED
wwang: 02/07/2011
alopez: 11/19/2010
wwang: 4/17/2009
ckniffin: 4/9/2009
terry: 4/3/2009
ckniffin: 4/3/2009
alopez: 1/20/2005
wwang: 1/19/2005
wwang: 1/13/2005
terry: 1/12/2005
ckniffin: 12/4/2003
carol: 11/6/2003
ckniffin: 11/3/2003