RBCC Red Blood Cell Collection

ASL [Confidence: low (only semi-automatic identification from reviews)]
Argininosuccinate lyase; ASAL; 4.3.2.1 (Arginosuccinase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P04424
ID ARLY_HUMAN Reviewed; 464 AA.
AC P04424; E7EMI0; E9PE48; Q6LDS5; Q96HS2;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Argininosuccinate lyase;
DE Short=ASAL;
DE EC=4.3.2.1;
DE AltName: Full=Arginosuccinase;
GN Name=ASL;
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=Liver;
RX PubMed=3391281; DOI=10.1016/0014-5793(88)80124-8;
RA Matuo S., Tatsuno M., Kobayashi K., Saheki T., Miyata T.;
RT "Isolation of cDNA clones of human argininosuccinate lyase and
RT corrected amino acid sequence.";
RL FEBS Lett. 234:395-399(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3463959; DOI=10.1073/pnas.83.19.7211;
RA O'Brien W.E., McInnes R., Kalumuck K., Adcock M.;
RT "Cloning and sequence analysis of cDNA for human argininosuccinate
RT lyase.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7211-7215(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2644168; DOI=10.1016/0888-7543(89)90314-5;
RA Todd S., McGill J.R., McCombs J.L., Moore C.M., Weider I.,
RA Naylor S.L.;
RT "cDNA sequence, interspecies comparison, and gene mapping analysis of
RT argininosuccinate lyase.";
RL Genomics 4:53-59(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Matuo S.;
RT "Cloning and sequence analysis of cDNA for human argininosuccinate
RT lyase.";
RL Kagoshima Daigaku Igaku Zasshi 40:147-160(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RA Linnebank M., Tschiedel E., Koch H.G.;
RT "Complete sequence of the human ASL gene.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Cervix;
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 [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 5-97 (ISOFORM 1/2/3).
RX PubMed=3368457; DOI=10.1073/pnas.85.10.3479;
RA Piatigorsky J., O'Brien W.E., Norman B.L., Kalumuck K., Wistow G.J.,
RA Borras T., Nickerson J.M., Wawrousek E.F.;
RT "Gene sharing by delta-crystallin and argininosuccinate lyase.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:3479-3483(1988).
RN [9]
RP ACETYLATION AT LYS-69 AND LYS-288, ENZYME REGULATION, MASS
RP SPECTROMETRY, AND MUTAGENESIS OF LYS-288.
RX PubMed=20167786; DOI=10.1126/science.1179689;
RA Zhao S., Xu W., Jiang W., Yu W., Lin Y., Zhang T., Yao J., Zhou L.,
RA Zeng Y., Li H., Li Y., Shi J., An W., Hancock S.M., He F., Qin L.,
RA Chin J., Yang P., Chen X., Lei Q., Xiong Y., Guan K.L.;
RT "Regulation of cellular metabolism by protein lysine acetylation.";
RL Science 327:1000-1004(2010).
RN [10]
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 [11]
RP X-RAY CRYSTALLOGRAPHY (4.2 ANGSTROMS).
RC TISSUE=Liver;
RX PubMed=9256435; DOI=10.1073/pnas.94.17.9063;
RA Turner M.A., Simpson A., McInnes R.R., Howell P.L.;
RT "Human argininosuccinate lyase: a structural basis for intragenic
RT complementation.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:9063-9068(1997).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF VARIANT ARG-286.
RX PubMed=11747432; DOI=10.1021/bi011525m;
RA Sampaleanu L.M., Vallee F., Thompson G.D., Howell P.L.;
RT "Three-dimensional structure of the argininosuccinate lyase frequently
RT complementing allele Q286R.";
RL Biochemistry 40:15570-15580(2001).
RN [13]
RP VARIANTS ARGINSA TRP-111; GLN-193 AND ARG-286, AND MUTAGENESIS.
RX PubMed=1705937;
RA Barbosa P., Cialkowski M., O'Brien W.E.;
RT "Analysis of naturally occurring and site-directed mutations in the
RT argininosuccinate lyase gene.";
RL J. Biol. Chem. 266:5286-5290(1991).
RN [14]
RP VARIANT ARGINSA CYS-95.
RX PubMed=2263616; DOI=10.1073/pnas.87.24.9625;
RA Walker D.C., McCloskey D.A., Simard L.R., McInnes R.R.;
RT "Molecular analysis of human argininosuccinate lyase: mutant
RT characterization and alternative splicing of the coding region.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:9625-9629(1990).
RN [15]
RP VARIANTS ARGINSA MET-178; CYS-379 AND CYS-385.
RX PubMed=12408190; DOI=10.1023/A:1020108002877;
RA Kleijer W.J., Garritsen V.H., Linnebank M., Mooyer P.,
RA Huijmans J.G.M., Mustonen A., Simola K.O.J., Arslan-Kirchner M.,
RA Battini R., Briones P., Cardo E., Mandel H., Tschiedel E.,
RA Wanders R.J.A., Koch H.G.;
RT "Clinical, enzymatic, and molecular genetic characterization of a
RT biochemical variant type of argininosuccinic aciduria: prenatal and
RT postnatal diagnosis in five unrelated families.";
RL J. Inherit. Metab. Dis. 25:399-410(2002).
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-181 AND VAL-200.
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 [17]
RP VARIANTS ARGINSA ASN-31; GLN-113; MET-178; GLN-186; TRP-236; ARG-286;
RP LEU-335; ARG-382 AND TRP-456.
RX PubMed=17326097; DOI=10.1002/humu.20498;
RA Trevisson E., Salviati L., Baldoin M.C., Toldo I., Casarin A.,
RA Sacconi S., Cesaro L., Basso G., Burlina A.B.;
RT "Argininosuccinate lyase deficiency: mutational spectrum in Italian
RT patients and identification of a novel ASL pseudogene.";
RL Hum. Mutat. 28:694-702(2007).
CC -!- CATALYTIC ACTIVITY: 2-(N(omega)-L-arginino)succinate = fumarate +
CC L-arginine.
CC -!- ENZYME REGULATION: Enzyme activity is regulated by acetylation (By
CC similarity).
CC -!- PATHWAY: Amino-acid biosynthesis; L-arginine biosynthesis; L-
CC arginine from L-ornithine and carbamoyl phosphate: step 3/3.
CC -!- PATHWAY: Nitrogen metabolism; urea cycle; L-arginine and fumarate
CC from (N(omega)-L-arginino)succinate: step 1/1.
CC -!- SUBUNIT: Homotetramer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P04424-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P04424-2; Sequence=VSP_047256;
CC Note=Gene prediction based on EST data;
CC Name=3;
CC IsoId=P04424-3; Sequence=VSP_047255;
CC Note=Gene prediction based on EST data;
CC -!- PTM: Acetylation modifies enzyme activity in response to
CC alterations of extracellular nutrient availability. Acetylation
CC increased with trichostin A (TSA) or with nicotinamide (NAM).
CC Glucose increases acetylation by about a factor of 3 with
CC decreasing enzyme activity. Acetylation on Lys-288 is decreased on
CC the addition of extra amino acids resulting in activation of
CC enzyme activity.
CC -!- DISEASE: Argininosuccinic aciduria (ARGINSA) [MIM:207900]: An
CC autosomal recessive disorder of the urea cycle. The disease is
CC characterized by mental and physical retardation, liver
CC enlargement, skin lesions, dry and brittle hair showing
CC trichorrhexis nodosa microscopically and fluorescing red,
CC convulsions, and episodic unconsciousness. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the lyase 1 family. Argininosuccinate lyase
CC subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA51786.1; Type=Frameshift; Positions=387, 452;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ASL";
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DR EMBL; Y00753; CAA68722.1; -; mRNA.
DR EMBL; M14218; AAA51786.1; ALT_FRAME; mRNA.
DR EMBL; J03058; AAA51787.1; -; mRNA.
DR EMBL; M57638; AAA51788.1; -; mRNA.
DR EMBL; AF376770; AAL57276.1; -; Genomic_DNA.
DR EMBL; AC068533; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC008195; AAH08195.1; -; mRNA.
DR EMBL; BC033146; AAH33146.1; -; mRNA.
DR EMBL; M21007; AAA35566.1; -; Genomic_DNA.
DR EMBL; M21006; AAA35566.1; JOINED; Genomic_DNA.
DR PIR; A31658; WZHURS.
DR RefSeq; NP_000039.2; NM_000048.3.
DR RefSeq; NP_001020114.1; NM_001024943.1.
DR RefSeq; NP_001020115.1; NM_001024944.1.
DR RefSeq; NP_001020117.1; NM_001024946.1.
DR UniGene; Hs.632015; -.
DR PDB; 1AOS; X-ray; 4.20 A; A/B=1-464.
DR PDB; 1K62; X-ray; 2.65 A; A/B=1-464.
DR PDBsum; 1AOS; -.
DR PDBsum; 1K62; -.
DR ProteinModelPortal; P04424; -.
DR SMR; P04424; 6-464.
DR IntAct; P04424; 5.
DR STRING; 9606.ENSP00000307188; -.
DR DrugBank; DB00125; L-Arginine.
DR PhosphoSite; P04424; -.
DR DMDM; 124028641; -.
DR PaxDb; P04424; -.
DR PRIDE; P04424; -.
DR DNASU; 435; -.
DR Ensembl; ENST00000304874; ENSP00000307188; ENSG00000126522.
DR Ensembl; ENST00000380839; ENSP00000370219; ENSG00000126522.
DR Ensembl; ENST00000395331; ENSP00000378740; ENSG00000126522.
DR Ensembl; ENST00000395332; ENSP00000378741; ENSG00000126522.
DR GeneID; 435; -.
DR KEGG; hsa:435; -.
DR UCSC; uc003tuq.3; human.
DR CTD; 435; -.
DR GeneCards; GC07P065540; -.
DR HGNC; HGNC:746; ASL.
DR HPA; CAB003696; -.
DR HPA; HPA016646; -.
DR MIM; 207900; phenotype.
DR MIM; 608310; gene.
DR neXtProt; NX_P04424; -.
DR Orphanet; 23; Argininosuccinic aciduria.
DR PharmGKB; PA25046; -.
DR eggNOG; COG0165; -.
DR HOGENOM; HOG000242744; -.
DR HOVERGEN; HBG004281; -.
DR InParanoid; P04424; -.
DR KO; K01755; -.
DR OMA; PTANSLD; -.
DR OrthoDB; EOG7PS1FN; -.
DR BioCyc; MetaCyc:HS10034-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P04424; -.
DR UniPathway; UPA00068; UER00114.
DR UniPathway; UPA00158; UER00273.
DR ChiTaRS; asl; human.
DR EvolutionaryTrace; P04424; -.
DR GenomeRNAi; 435; -.
DR NextBio; 1821; -.
DR PRO; PR:P04424; -.
DR ArrayExpress; P04424; -.
DR Bgee; P04424; -.
DR CleanEx; HS_ASL; -.
DR Genevestigator; P04424; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004056; F:argininosuccinate lyase activity; EXP:Reactome.
DR GO; GO:0019676; P:ammonia assimilation cycle; IEA:Ensembl.
DR GO; GO:0042450; P:arginine biosynthetic process via ornithine; IEA:InterPro.
DR GO; GO:0006527; P:arginine catabolic process; TAS:ProtInc.
DR GO; GO:0006475; P:internal protein amino acid acetylation; IDA:UniProtKB.
DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0000050; P:urea cycle; TAS:Reactome.
DR Gene3D; 1.10.275.10; -; 1.
DR InterPro; IPR009049; Argininosuccinate_lyase.
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 PANTHER; PTHR11444; PTHR11444; 1.
DR PANTHER; PTHR11444:SF3; PTHR11444:SF3; 1.
DR Pfam; PF00206; Lyase_1; 1.
DR PRINTS; PR00149; FUMRATELYASE.
DR SUPFAM; SSF48557; SSF48557; 1.
DR TIGRFAMs; TIGR00838; argH; 1.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Amino-acid biosynthesis; Arginine biosynthesis; Complete proteome;
KW Disease mutation; Lyase; Polymorphism; Reference proteome; Urea cycle.
FT CHAIN 1 464 Argininosuccinate lyase.
FT /FTId=PRO_0000137712.
FT MOD_RES 69 69 N6-acetyllysine.
FT MOD_RES 288 288 N6-acetyllysine.
FT VAR_SEQ 176 201 Missing (in isoform 3).
FT /FTId=VSP_047255.
FT VAR_SEQ 307 326 Missing (in isoform 2).
FT /FTId=VSP_047256.
FT VARIANT 31 31 D -> N (in ARGINSA).
FT /FTId=VAR_043106.
FT VARIANT 95 95 R -> C (in ARGINSA; dbSNP:rs28940585).
FT /FTId=VAR_000676.
FT VARIANT 111 111 R -> W (in ARGINSA).
FT /FTId=VAR_000677.
FT VARIANT 113 113 R -> Q (in ARGINSA).
FT /FTId=VAR_043107.
FT VARIANT 178 178 V -> M (in ARGINSA; dbSNP:rs28941473).
FT /FTId=VAR_017572.
FT VARIANT 181 181 T -> S (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036281.
FT VARIANT 186 186 R -> Q (in ARGINSA).
FT /FTId=VAR_043108.
FT VARIANT 193 193 R -> Q (in ARGINSA).
FT /FTId=VAR_000678.
FT VARIANT 200 200 G -> V (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036282.
FT VARIANT 236 236 R -> W (in ARGINSA).
FT /FTId=VAR_043109.
FT VARIANT 286 286 Q -> R (in ARGINSA; dbSNP:rs28941472).
FT /FTId=VAR_000679.
FT VARIANT 335 335 V -> L (in ARGINSA).
FT /FTId=VAR_043110.
FT VARIANT 379 379 R -> C (in ARGINSA; dbSNP:rs28940287).
FT /FTId=VAR_017573.
FT VARIANT 382 382 M -> R (in ARGINSA).
FT /FTId=VAR_043111.
FT VARIANT 385 385 R -> C (in ARGINSA; dbSNP:rs28940286).
FT /FTId=VAR_017574.
FT VARIANT 456 456 R -> W (in ARGINSA).
FT /FTId=VAR_043112.
FT MUTAGEN 51 51 K->N: 2-fold reduction in activity.
FT MUTAGEN 89 89 H->Q: 10-fold reduction in activity.
FT MUTAGEN 288 288 K->R: Refractory to inhibition by TSA and
FT NAM and by addition of extra amino acids.
FT No effect on protein structure.
FT CONFLICT 246 246 A -> R (in Ref. 1; CAA68722, 2; AAA51786,
FT 3; AAA51787, 4; AAA51788 and 5;
FT AAL57276).
FT CONFLICT 431 431 G -> R (in Ref. 1; CAA68722).
FT HELIX 19 25
FT HELIX 28 31
FT HELIX 32 34
FT HELIX 35 51
FT HELIX 57 76
FT HELIX 88 100
FT HELIX 101 106
FT TURN 107 110
FT HELIX 113 150
FT STRAND 154 159
FT STRAND 162 168
FT HELIX 169 194
FT STRAND 195 197
FT TURN 202 205
FT HELIX 213 219
FT STRAND 223 225
FT HELIX 229 232
FT HELIX 237 264
FT TURN 266 268
FT HELIX 291 314
FT HELIX 323 327
FT HELIX 328 352
FT HELIX 357 362
FT HELIX 366 369
FT HELIX 370 379
FT HELIX 384 400
FT HELIX 405 407
FT HELIX 410 414
FT HELIX 423 428
FT HELIX 430 434
FT STRAND 442 444
FT HELIX 445 463
SQ SEQUENCE 464 AA; 51658 MW; F751625C1A581883 CRC64;
MASESGKLWG GRFVGAVDPI MEKFNASIAY DRHLWEVDVQ GSKAYSRGLE KAGLLTKAEM
DQILHGLDKV AEEWAQGTFK LNSNDEDIHT ANERRLKELI GATAGKLHTG RSRNDQVVTD
LRLWMRQTCS TLSGLLWELI RTMVDRAEAE RDVLFPGYTH LQRAQPIRWS HWILSHAVAL
TRDSERLLEV RKRINVLPLG SGAIAGNPLG VDRELLRAEL NFGAITLNSM DATSERDFVA
EFLFWASLCM THLSRMAEDL ILYCTKEFSF VQLSDAYSTG SSLMPQKKNP DSLELIRSKA
GRVFGRCAGL LMTLKGLPST YNKDLQEDKE AVFEVSDTMS AVLQVATGVI STLQIHQENM
GQALSPDMLA TDLAYYLVRK GMPFRQAHEA SGKAVFMAET KGVALNQLSL QELQTISPLF
SGDVICVWDY GHSVEQYGAL GGTARSSVDW QIRQVRALLQ AQQA
//

MIM 207900
*RECORD*
*FIELD* NO
207900
*FIELD* TI
#207900 ARGININOSUCCINIC ACIDURIA
;;ARGININOSUCCINASE DEFICIENCY;;
ARGININOSUCCINATE LYASE DEFICIENCY;;
read moreASL DEFICIENCY;;
ARGININOSUCCINIC ACID LYASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because argininosuccinic
aciduria is caused by mutation in the gene encoding argininosuccinate
lyase (ASL; 608310).

DESCRIPTION

Argininosuccinic aciduria is an autosomal recessive disorder of the urea
cycle. Urea cycle disorders are characterized by the triad of
hyperammonemia, encephalopathy, and respiratory alkalosis. Five
disorders involving different defects in the biosynthesis of the enzymes
of the urea cycle have been described: ornithine transcarbamylase
deficiency (311250), carbamyl phosphate synthetase deficiency (237300),
argininosuccinate synthetase deficiency, or citrullinemia (215700),
argininosuccinate lyase deficiency, and arginase deficiency (207800).

Erez (2013) reviewed argininosuccinic aciduria and progress in
understanding it as a monogenic disorder that, like other inborn errors
of metabolism, manifests as a multifactorial disorder at the phenotypic
level.

CLINICAL FEATURES

Two forms of argininosuccinic aciduria have been recognized: an
early-onset, or malignant, type and a late-onset type.

As originally described by Allan et al. (1958), onset of symptoms of
argininosuccinic aciduria occurs in the first weeks of life. Features
include mental and physical retardation, convulsions, episodic
unconsciousness, liver enlargement, skin lesions, and dry and brittle
hair showing trichorrhexis nodosa microscopically and fluorescing red.
Coryell et al. (1964) reported familial association of argininosuccinic
aciduria. They noted that in the U.S., where arginine is probably
supplied adequately by the usual diet, brittle hair may not occur as
often as in Great Britain, where the average protein intake is less
ample. Shih et al. (1969) reported deficiency of argininosuccinase in
cultured fibroblasts from patients.

Lewis and Miller (1970) described the neuropathologic changes in
argininosuccinic aciduria. They noted that astrocyte transformation to
Alzheimer type II glia may be a consistent feature of any form of
hyperammonemia. Postmortem liver showed marked deficiency of
argininosuccinate lyase.

Asai et al. (1997) described fatal hyperammonemia in a child with
argininosuccinic aciduria following enflurane anesthesia. The diagnosis
of argininosuccinic aciduria had been made while the patient was
hospitalized for febrile seizures at the age of 18 months. Plasma
argininosuccinate was markedly elevated. Argininosuccinase activity was
absent in her erythrocytes and was within the heterozygous range in both
parents. Oral arginine supplementation and a low protein diet were
started. At 13 years of age, the patient underwent an inguinal
hernioplasty. The preoperative state was satisfactory except for
hepatomegaly and mental retardation. All routine investigations were
normal, including those for ammonia. During the second evening after
operation, the patient became lethargic with frequent convulsions
despite adequate levels of the 3 antiepileptics on which she had been
maintained for many years. Despite intravenous hypertonic glucose and
arginine supplementation, her ammonia level rose greatly and she became
comatose. Despite repeated hemodialysis, she died on the sixth
postoperative day. Hepatic findings were consistent with fatty changes.
Asai et al. (1997) suggested that although it was tempting to conclude
that only enflurane was directly responsible for the hyperammonemia in
the patient and although this relationship was not proved beyond
reasonable doubt, general anesthesia, including enflurane, should be
avoided in patients with argininosuccinic aciduria.

Kleijer et al. (2002) reported a biochemical variant of
argininosuccinate lyase deficiency found in 5 individuals. In comparison
to classic cases, the variant cases of argininosuccinate lyase
deficiency were characterized by residual enzyme activity as measured by
the incorporation of C-14-citrulline into proteins. The 5 patients of
different ethnic backgrounds presented with relatively mild clinical
symptoms, variable age of onset, marked argininosuccinic aciduria, and
severe, but not complete, deficiency of argininosuccinate lyase.
C14-citrulline incorporation into proteins, which is completely blocked
in classic argininosuccinic aciduria, was only partially reduced in
fibroblasts of these patients. All of these patients were found to have
mutations in the ASL gene (see, e.g., 608310.0004-608310.0006). The
authors concluded that there are patients of different ethnic
backgrounds who are characterized by residual activity of
argininosuccinate lyase and who present with less severe clinical
course.

DIAGNOSIS

- Prenatal Diagnosis

Pijpers et al. (1990) established the diagnosis of argininosuccinic
aciduria in both fetuses of a dizygotic pregnancy, using transabdominal
chorionic villus sampling at 10 weeks' gestation. Kleijer et al. (2002)
performed successful molecular prenatal diagnosis in 3 affected
families.

CLINICAL MANAGEMENT

Brusilow and Batshaw (1979) reported success with arginine treatment in
argininosuccinase deficiency. The treatment favors the formation of
argininosuccinic acid (ASA); since ASA contains the 2 waste nitrogen
atoms later excreted in urea in healthy persons, and since it has a
renal clearance similar to the glomerular filtration rate, the authors
reasoned that hyperammonemia might be relieved by arginine therapy,
provided stoichiometric amounts of ornithine are available.

Kvedar et al. (1991) observed 'normalization' of hair shafts after
patients were treated with a low protein, arginine-supplemented diet.
Widhalm et al. (1992) described a follow-up of 12 Austrian children
detected since 1973 in a national neonate screening program. All were
managed with a daily arginine supplement in conjunction with either a
normal diet or a special diet in which protein intake was restricted.
They found that early treatment of partial argininosuccinate lyase
deficiency resulted in normal intellectual and psychomotor development.

Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the
second most common urea cycle disorder, and leads to deficiency of both
ureagenesis and nitric oxide (NO) production. Subjects with ASA have
been reported to develop long-term complications such as hypertension
and neurocognitive deficits despite early initiation of therapy and the
absence of documented hyperammonemia. In an ASA subject with severe
hypertension refractory to antihypertensive medications, Nagamani et al.
(2012) showed that monotherapy with NO supplements (isosorbide
dinitrate) resulted in the long-term control of hypertension and a
decrease in cardiac hypertrophy. In addition, the NO therapy was
associated with an improvement in some neuropsychologic parameters
pertaining to verbal memory and nonverbal problem solving. Nagamani et
al. (2012) concluded that ASA, in addition to being a classical urea
cycle disorder, is also a model of congenital human NO deficiency and
that ASA subjects could potentially benefit from NO supplementation,
which should be investigated for the long-term treatment of this
condition.

MOLECULAR GENETICS

- Early Identification of Complementation Groups

In study of 5 cell lines from patients with argininosuccinate lyase
deficiency, Cathelineau et al. (1981) observed 2 complementation groups.
Since the restoration of activity was not total, the complementation was
assumed to be intragenic.

McInnes et al. (1984) performed complementation analysis in a search for
genetic heterogeneity in this disorder. In 20 of 28 fibroblast strains
cultured from patients with ASL deficiency, partial complementation was
observed, with 2- to 10-fold increases in lyase activity. The data
suggested that all the mutants were affected at a single locus, which
the authors suggested was the structural gene coding for that enzyme.
McInnes et al. (1984) presented a complementation map of the gene. The
authors noted that there are few examples of interallelic
complementation in human genetics: galactosemia (230400) and
propionyl-CoA-carboxylase deficiency (606054) are among them. ASL is a
homotetramer; in microorganisms, interallelic complementation has been
found to be almost universal at loci coding for homomultimeric proteins.
The same group (Simard et al., 1986) found differing levels of ASL
cross-reactive material (CRM) in different fibroblast lines, suggesting
the presence of multiple lyase mutant monomers and mutations underlying
ASL deficiency. Many of these mutants were indistinguishable by
clinical, enzymatic, or complementation analysis.

In 15 unrelated patients who were compound heterozygotes for mutations
at the ASL locus, Linnebank et al. (2002) could find no evidence that
interallelic complementation plays a major role for modifying
biochemical phenotypes.

- Disease-Causing Mutations

In a patient with ASL deficiency, born of a consanguineous mating,
Walker et al. (1990) identified a homozygous mutation in the ASL gene
(608310.0001). The residual activity of the mutant enzyme was about 1%.

In 27 unrelated patients with ASL deficiency, Linnebank et al. (2002)
identified 23 different mutations, 19 novel, in the ASL gene. Fifteen of
the 54 alleles had an IVS5+1G-A splice site mutation (608310.0003).

In 5 patients with a biochemical variant of ASL deficiency in which
there was residual enzyme activity and mild clinical symptoms, Kleijer
et al. (2002) identified several mutations in the ASL gene. R385C
(608310.0004), V178M (608310.0005), and R379C (608310.0006) were
detected in homozygous states, whereas 1 patient was compound
heterozygous for 2 known mutations, including Q286R (608310.0002).
Prenatal diagnosis was successfully performed in 3 of the families.

Trevisson et al. (2007) identified 16 different mutations in the ASL
gene, including 14 novel mutations, in 12 Italian patients from 10
families with ASL deficiency. All patients tested, except 1, had less
than 5% residual enzyme activity. Mutations were scattered throughout
the gene, but there were no genotype/phenotype correlations.

POPULATION GENETICS

The prevalence of argininosuccinic aciduria is estimated to be 1 in
150,000 (Testai and Gorelick, 2010).

*FIELD* SA
Bohles et al. (1978); Collins et al. (1980); Fleisher et al. (1979);
Glick et al. (1976); Goodman et al. (1973); Kint and Carton (1968);
Levin (1967); Levin et al. (1961); Moser et al. (1967); Qureshi et
al. (1978); Van der Heiden et al. (1976)
*FIELD* RF
1. Allan, J. D.; Cusworth, D. C.; Dent, C. E.; Wilson, V. K.: A disease,
probably hereditary, characterized by severe mental deficiency and
a constant gross abnormality of amino acid metabolism. Lancet 271:
182-187, 1958. Note: Originally Volume I.

2. Asai, K.; Ishii, S.; Ohta, S.; Furusho, K.: Fatal hyperammonaemia
in argininosuccinic aciduria following enflurane anaesthesia. (Letter) Europ.
J. Paediat. 157: 169-170, 1997.

3. Bohles, H.; Heid, H.; Harms, D.; Schmid, D.; Fekl, W.: Argininosuccinic
aciduria: metabolic studies and effects of treatment with keto-analogues
of essential amino acids. Europ. J. Pediat. 128: 225-233, 1978.

4. Brusilow, S. W.; Batshaw, M. L.: Arginine therapy of argininosuccinase
deficiency. Lancet 313: 124-127, 1979. Note: Originally Volume I.

5. Cathelineau, L.; Dinh, D. P.; Briand, P.; Kamoun, P.: Studies
on complementation in argininosuccinate synthetase and argininosuccinate
lyase deficiencies in human fibroblasts. Hum. Genet. 57: 282-284,
1981.

6. Collins, F. S.; Summer, G. K.; Schwartz, R. P.; Parke, J. C., Jr.
: Neonatal argininosuccinic aciduria--survival after early diagnosis
and dietary management. J. Pediat. 96: 429-431, 1980.

7. Coryell, M. E.; Hall, W. K.; Thevaos, T. G.; Welter, D. A.; Gatz,
A. J.; Horton, B. F.; Sisson, B. D.; Looper, J. W., Jr.; Farrow, R.
T.: Familial study of human enzyme defect, argininosuccinic aciduria. Biochem.
Biophys. Res. Commun. 14: 307-312, 1964.

8. Erez, A.: Argininosuccinic aciduria: from a monogenic to a complex
disorder. Genet. Med. 15: 251-257, 2013.

9. Fleisher, L. D.; Rassin, D. K.; Desnick, R. J.; Salwen, H. R.;
Rogers, P.; Bean, M.; Gaull, G. E.: Argininosuccinic aciduria: prenatal
studies in a family at risk. Am. J. Hum. Genet. 31: 439-445, 1979.

10. Glick, N. R.; Snodgrass, P. J.; Schafer, I. A.: Neonatal argininosuccinic
aciduria with normal brain and kidney but absent liver argininosuccinate
lyase activity. Am. J. Hum. Genet. 28: 22-30, 1976.

11. Goodman, S. I.; Mace, J. W.; Turner, B.; Garrett, W. J.: Antenatal
diagnosis of argininosuccinic aciduria. Clin. Genet. 4: 236-240,
1973.

12. Kint, J. A.; Carton, D.: Deficient argininosuccinase activity
in brain in argininosuccinicaciduria. (Letter) Lancet 292: 635 only,
1968. Note: Originally Volume II.

13. Kleijer, W. J.; Garritsen, V. H.; Linnebank, M.; Mooyer, P.; Huijmans,
J. G. M.; Mustonen, A.; Simola, K. O. J.; Arslan-Kirchner, M.; Battini,
R.; Briones, P.; Cardo, E.; Mandel, H.; Tschiedel, E.; Wanders, R.
J. A.; Koch, H. G.: Clinical, enzymatic, and molecular genetic characterization
of a biochemical variant type of argininosuccinic aciduria: prenatal
and postnatal diagnosis in 5 unrelated families. J. Inherit. Metab.
Dis. 25: 399-410, 2002.

14. Kvedar, J. C.; Baden, H. P.; Baden, L. A.; Shih, V. E.; Kolodny,
E. H.: Dietary management reverses grooving and abnormal polarization
of hair shafts in argininosuccinase deficiency. Am. J. Med. Genet. 40:
211-213, 1991.

15. Levin, B.: Argininosuccinic aciduria. Am. J. Dis. Child. 113:
162-165, 1967.

16. Levin, B.; MacKay, H. M.; Oberholzer, V. G.: Argininosuccinic
aciduria: an inborn error of amino acid metabolism. Arch. Dis. Child. 36:
622-632, 1961.

17. Lewis, P. D.; Miller, A. L.: Argininosuccinic aciduria: case
report with neuropathological findings. Brain 93: 413-422, 1970.

18. Linnebank, M.; Tschiedel, E.; Haberle, J.; Linnebank, A.; Willenbring,
H.; Kleijer, W. J.; Koch, H. G.: Argininosuccinate lyase (ASL) deficiency:
mutation analysis in 27 patients and a completed structure of the
human ASL gene. Hum. Genet. 111: 350-359, 2002.

19. McInnes, R. R.; Shih, V.; Chilton, S.: Interallelic complementation
in an inborn error of metabolism: genetic heterogeneity in argininosuccinate
lyase deficiency. Proc. Nat. Acad. Sci. 81: 4480-4484, 1984.

20. Moser, H. W.; Efron, M. L.; Brown, H.; Diamond, R.; Neumann, C.
G.: Argininosuccinic aciduria: report of two cases and demonstration
of intermittent elevation of blood ammonia. Am. J. Med. 42: 9-26,
1967.

21. Nagamani, S. C. S.; Campeau, P. M.; Shchelochkov, O. A.; Premkumar,
M. H.; Guse, K.; Brunetti-Pierri, N.; Chen, Y.; Sun, Q.; Tang, Y.;
Palmer, D.; Reddy, A. K.; Li, L.; and 9 others: Nitric-oxide supplementation
for treatment of long-term complications in argininosuccinic aciduria. Am.
J. Hum. Genet. 90: 836-846, 2012.

22. Pijpers, L.; Kleijer, W. J.; Reuss, A.; Jahoda, M. G. J.; Los,
F. J.; Sachs, E. S.; Wladimiroff, J. W.: Transabdominal chorionic
villus sampling in a multiple pregnancy at risk of argininosuccinic
aciduria: a case report. Am. J. Med. Genet. 36: 449-450, 1990.

23. Qureshi, I. A.; Letarte, J.; Ouellet, R.; Lemieux, B.: Enzymologic
and metabolic studies in two families affected by argininosuccinic
aciduria. Pediat. Res. 12: 256-262, 1978.

24. Shih, V. E.; Littlefield, J. W.; Moser, H. W.: Argininosuccinase
deficiency in fibroblasts cultured from patients with argininosuccinic
aciduria. Biochem. Genet. 3: 81-83, 1969.

25. Simard, L.; O'Brien, W. E.; McInnes, R. R.: Argininosuccinate
lyase deficiency: evidence for heterogeneous structural gene mutations
by immunoblotting. Am. J. Hum. Genet. 39: 38-51, 1986.

26. Testai, F. D.; Gorelick, P. B.: Inherited metabolic disorders
and stroke part 2: homocystinuria, organic acidurias, and urea cycle
disorders. Arch. Neurol. 67: 148-153, 2010.

27. Trevisson, E.; Salviati, L.; Baldoin, M. C.; Toldo, I.; Casarin,
A.; Sacconi, S.; Cesaro, L.; Basso, G.; Burlina, A. B.: Argininosuccinate
lyase deficiency: mutational spectrum in Italian patients and identification
of a novel ASL pseudogene. Hum. Mutat. 28: 694-702, 2007.

28. Van der Heiden, C.; Gerards, L. J.; van Biervliet, J. P. G. M.;
Desplanque, J.; DeBree, P. K.; Van Sprang, F. J.; Wadman, S. K.:
Lethal neonatal argininosuccinate lyase deficiency in four children
from one sibship. Helv. Paediat. Acta 31: 407-417, 1976.

29. Walker, D. C.; McCloskey, D. A.; Simard, L. R.; McInnes, R. R.
: Molecular analysis of human argininosuccinate lyase: mutant characterization
and alternative splicing of the coding region. Proc. Nat. Acad. Sci. 87:
9625-9629, 1990.

30. Widhalm, K.; Koch, S.; Scheibenreiter, S.; Knoll, E.; Colombo,
J. P.; Bachmann, C.; Thalhammer, O.: Long-term follow-up of 12 patients
with the late-onset variant of argininosuccinic acid lyase deficiency:
no impairment of intellectual and psychomotor development during therapy. Pediatrics 89:
1182-1184, 1992.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

ABDOMEN:
[Liver];
Hepatic fibrosis;
Hepatomegaly;
Elevated serum glutamic oxaloacetic transaminase (SGOT);
Elevated serum glutamic pyruvic transaminase (SGPT);
[Gastrointestinal];
Poor feeding;
Protein avoidance;
Vomiting

SKIN, NAILS, HAIR:
[Hair];
Trichorrhexis nodosa;
Dry brittle hair

NEUROLOGIC:
[Central nervous system];
Ataxia;
Coma;
Seizures;
Cerebral edema;
Developmental delay;
Mental retardation;
[Behavioral/psychiatric manifestations];
Irritability;
Lethargy

METABOLIC FEATURES:
Episodic ammonia intoxication;
Respiratory alkalosis;
Arginine deficiency

LABORATORY ABNORMALITIES:
Hyperammonemia;
High plasma citrulline (100-300 micromolar);
High plasma glutamine;
Hepatic argininosuccinase deficiency;
Argininosuccinicaciduria;
Elevated serum glutamic oxaloacetic transaminase (SGOT);
Elevated serum glutamic pyruvic transaminase (SGPT);
Orotic aciduria

MISCELLANEOUS:
Onset in neonatal period or infancy;
Prevalence is estimated to be 1 in 150,000

MOLECULAR BASIS:
Caused by mutation in the argininosuccinate lyase gene (ASL, 608310.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/11/2010
Ada Hamosh - revised: 10/5/1999

*FIELD* ED
joanna: 10/22/2013
joanna: 10/26/2010
ckniffin: 10/11/2010
ckniffin: 9/11/2007
joanna: 4/30/2004
joanna: 10/5/1999

*FIELD* CN
Ada Hamosh - updated: 5/1/2013
Ada Hamosh - updated: 7/25/2012
Cassandra L. Kniffin - updated: 10/11/2010
Cassandra L. Kniffin - updated: 8/20/2007
Cassandra L. Kniffin - reorganized: 12/4/2003
Ada Hamosh - updated: 10/7/2003
Victor A. McKusick - updated: 11/13/2002
Victor A. McKusick - updated: 5/3/1999
Victor A. McKusick - updated: 11/2/1998

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
alopez: 05/01/2013
alopez: 5/1/2013
alopez: 8/1/2012
terry: 7/25/2012
wwang: 10/29/2010
ckniffin: 10/11/2010
terry: 2/11/2009
wwang: 9/5/2007
ckniffin: 8/20/2007
alopez: 5/29/2007
terry: 4/18/2005
carol: 12/4/2003
ckniffin: 12/3/2003
cwells: 10/7/2003
tkritzer: 11/22/2002
tkritzer: 11/15/2002
terry: 11/13/2002
carol: 6/22/2001
carol: 9/22/1999
mgross: 5/6/1999
terry: 5/3/1999
carol: 11/11/1998
terry: 11/2/1998
mimadm: 11/12/1995
davew: 8/26/1994
carol: 4/12/1994
carol: 7/24/1992
carol: 7/23/1992
supermim: 3/16/1992

MIM 608310
*RECORD*
*FIELD* NO
608310
*FIELD* TI
*608310 ARGININOSUCCINATE LYASE; ASL
;;ARGININOSUCCINASE
*FIELD* TX

DESCRIPTION

The ASL gene encodes the subunit of argininosuccinate lyase (EC 4.3.2.1)
read moreis a urea cycle enzyme that catalyzes the cleavage of argininosuccinate
to fumarate and arginine, an essential step in the process of
detoxification of ammonia via the urea cycle (O'Brien et al., 1986).

CLONING

Using antibodies specific for argininosuccinate lyase to screen a human
liver cDNA library, O'Brien et al. (1986) isolated a cDNA corresponding
to the human ASL gene. The cDNA encodes a deduced protein of 463 amino
acids with a predicted molecular mass of 52 kD, and the active enzyme is
a homotetramer. The amino acid sequence of the human enzyme shows 56%
homology to the yeast enzyme. Matuo et al. (1988) isolated clones of
human ASL cDNA and determined the nucleotide sequence. They corrected
some minor errors in the sequence reported by O'Brien et al. (1986).

Abramson et al. (1991) found that the DNA sequences encoded by exon 7
were deleted in approximately 5 to 10% of the mature mRNA in all tissue
sources examined, suggesting alternative splicing. Walker et al. (1990)
presented evidence for an alternatively spliced ASL transcript in which
exon 2 is removed.

GENE STRUCTURE

Abramson et al. (1991) demonstrated that the ASL gene contains 16 exons.
The exon structure of the gene is identical to that of the rat and
similar to that of the delta-crystallin genes in the chicken.

Linnebank et al. (2002) completed the structure and sequence of the ASL
gene and determined that it has 17 exons. The first, exon zero (0),
codes only for the 5-untranslated region.

GENE FUNCTION

Zhao et al. (2010) showed that lysine acetylation is a prevalent
modification in enzymes that catalyze intermediate metabolism in the
human liver. Virtually every enzyme in glycolysis, gluconeogenesis, the
tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism,
and glycogen metabolism was found to be acetylated in human liver
tissue. The concentration of metabolic fuels, such as glucose, amino
acids, and fatty acids, influenced the acetylation status of metabolic
enzymes. Acetylation activated enoyl-coenzyme A
hydratase/3-hydroxyacyl-coenzyme A dehydrogenase (607037) in fatty acid
oxidation and malate dehydrogenase (see 154200) in the TCA cycle,
inhibited argininosuccinate lyase in the urea cycle, and destabilized
phosphoenolpyruvate carboxykinase (261680) in gluconeogenesis. Zhao et
al. (2010) concluded that acetylation plays a major role in metabolic
regulation.

MAPPING

Naylor et al. (1978) assigned the gene for ASL to chromosome 7. By
analysis of genomic DNA from hamster-human cell hybrids, O'Brien et al.
(1986) assigned the ASL gene to chromosome 7. By in situ hybridization,
Todd et al. (1989) mapped ASL to 7cen-q11.2.

- Pseudogene

O'Brien et al. (1986) found that the 5-prime end of the ASL cDNA was
also hybridized to a site on chromosome 22, which the authors assumed to
be a pseudogene. Todd et al. (1989) also detected a sequence on
chromosome 22.

Linnebank et al. (2002) identified a complete ASL homolog on chromosome
22q11.2 and stated that this so-called pseudogene is a regular gene with
a promoter region, a poly-A signal, and 11 exons containing a typical
initial exon and a terminal exon. The predicted coding sequence of the
pseudogene shared more than 0.4 kb high homology with ASL cDNA. A
GenBank search with a predicted cDNA revealed that the pseudogene might
encode immunoglobulin-lambda-like mRNA (IGLL1; 146770).

Trevisson et al. (2007) identified a second ASL pseudogene located on
chromosome 7 about 3 Mb upstream of the ASL gene, close to the
centromere. There was no evidence of expression of this second
pseudogene.

MOLECULAR GENETICS

In fibroblasts from a patient with ASL deficiency (207900) whose parents
were consanguineous, Walker et al. (1990) identified a homozygous
mutation in the ASL gene (608310.00001).

In 27 unrelated patients with ASL deficiency, Linnebank et al. (2002)
identified 23 different mutations, 19 novel, in the ASL gene. Fifteen of
the 54 alleles had an IVS5+1G-A splice site mutation (608310.0003).

In 5 patients with a biochemical variant of ASL deficiency in which
there was residual enzyme activity and mild clinical symptoms, Kleijer
et al. (2002) identified several mutations in the ASL gene. R385C
(608310.0004), V178M (608310.0005), and R379C (608310.0006) were
detected in homozygous states, whereas 1 patient was compound
heterozygous for 2 known mutations, including Q286R (608310.0002).
Prenatal diagnosis was successfully performed in 3 of the families.

Trevisson et al. (2007) identified 16 different mutations in the ASL
gene, including 14 novel mutations, in 12 Italian patients from 10
families with ASL deficiency. All patients tested, except 1, had less
than 5% residual enzyme activity. Mutations were scattered throughout
the gene, but there were no genotype/phenotype correlations.

EVOLUTION

Piatigorsky et al. (1988) demonstrated an extraordinary similarity
between the structural protein delta-crystallin of the lens of the duck
and the enzyme argininosuccinate lyase. Delta-crystallin is the dominant
crystallin in the lenses of birds and reptiles, but is absent from
lenses of mammals. It appears that birds, being uricotelic, have
relatively little use for the metabolic enzyme but use the protein as a
structural element by producing very large amounts. Southern blot
hybridization experiments with chicken delta-crystallin cDNA and human
ASL cDNA, coupled with enzymatic tests, provided strong evidence that
the crystallin and the enzyme share genes in an unusual evolutionary
strategy. 'Gene sharing' was the designation given this phenomenon,
i.e., when 2 distinct protein phenotypes are produced by the same
transcriptional unit. Once an enzyme has been recruited to serve as a
structural protein in lens, in addition to its conserved role in
metabolism, it is subject to at least 2 independent sets of evolutionary
pressure. This may lead to sequence modifications that enhance its
function as a crystallin, or gene duplication may take place with
subsequent partial separation of function (Piatigorsky and Wistow,
1991).

ANIMAL MODEL

Erez et al. (2011) created a hypomorphic mouse model of ASL deficiency
and showed that this mouse has a distinct phenotype of multiorgan
dysfunction and nitric oxide deficiency. Administration of nitrite,
which can be converted into nitric oxide in vivo, rescued the
manifestations of nitric oxide deficiency in hypomorphic Asl mice, and a
nitric oxide synthase-independent nitric oxide donor restored nitric
oxide-dependent vascular reactivity in humans with ASL deficiency.
Mechanistic studies showed that ASL has a structural function in
addition to the catalytic activity, by which it contributes to the
formation of a multiprotein complex required for nitric oxide
production. Erez et al. (2011) concluded their data demonstrated an
unappreciated role for ASL in nitric oxide synthase function and nitric
oxide homeostasis.

Nagamani et al. (2012) performed liver-directed gene therapy in a mouse
model of argininosuccinic aciduria (ASA) to distinguish the relative
contributions of the hepatic urea cycle defect from those of the nitric
oxide deficiency in the ASA phenotype. Whereas the gene therapy
corrected the ureagenesis defect, the systemic hypertension in mice
could be corrected by treatment with an exogenous NO source.

*FIELD* AV
.0001
ARGININOSUCCINIC ACIDURIA
ASL, ARG95CYS

In fibroblasts from a patient with late-onset ASL deficiency (207900)
who was the product of a consanguineous mating, Walker et al. (1990)
identified a homozygous 283C-T change in exon 3 of the ASL gene,
resulting in an arg95-to-cys (R95C) substitution within a 13-residue
stretch that is identical in yeast and human ASL. Enzyme activity of the
mutant protein was about 1%.

.0002
ARGININOSUCCINIC ACIDURIA
ASL, GLN286ARG

In a cell line from a patient with neonatal-onset of argininosuccinic
aciduria (207900) whose parents were consanguineous, Walker et al.
(1990) identified an 857A-G transition in exon 11 of the ASL gene,
resulting in a gln286-to-arg (Q286R) substitution. The mutation occurred
in a region of 18 amino acids identical in yeast and human ASL, and in a
region of 10 amino acids highly conserved in the family of class II
fumarases. The mutant enzyme retained less than 3% of residual ASL
activity.

.0003
ARGININOSUCCINIC ACIDURIA
ASL, IVS5, G-A, +1

Linnebank et al. (2002) found that 15 of 54 ASL deficiency
(207900)-related alleles had an IVS5+1G-A splice site mutation that
resulted in the deletion of 21 amino acids.

.0004
ARGININOSUCCINIC ACIDURIA
ASL, ARG385CYS

In 2 patients from a family with variable age of onset of ASL deficiency
(207900) and considerable residual ASL activity, Kleijer et al. (2002)
identified a homozygous 1153C-T transition, resulting in an
arg385-to-cys (R385C) substitution.

.0005
ARGININOSUCCINIC ACIDURIA
ASL, VAL178MET

In a patient from a family with variable age of onset of ASL deficiency
(207900) and considerable residual ASL activity, Kleijer et al. (2002)
identified a homozygous 532G-A transition in the ASL gene, resulting in
a val178-to-met (V178M) substitution.

.0006
ARGININOSUCCINIC ACIDURIA
ASL, ARG379CYS

In a patient from a family with variable age of onset of ASL deficiency
(207900) and considerable residual ASL activity, Kleijer et al. (2002)
identified a homozygous 1135C-T transition in the ASL gene, resulting in
an arg379-to-cys (R379C) substitution.

*FIELD* SA
Walker et al. (1989)
*FIELD* RF
1. Abramson, R. D.; Barbosa, P.; Kalumuck, K.; O'Brien, W. E.: Characterization
of the human argininosuccinate lyase gene and analysis of exon skipping. Genomics 10:
126-132, 1991.

2. Erez, A.; Nagamani, S. C. S.; Shchelochkov, O. A.; Premkumar, M.
H.; Campeau, P. M.; Chen, Y.; Garg, H. K.; Li, L.; Mian, A.; Bertin,
T. K.; Black, J. O.; Zeng, H.; and 10 others: Requirement of argininosuccinate
lyase for systemic nitric oxide production. Nature Med. 17: 1619-1626,
2011.

3. Kleijer, W. J.; Garritsen, V. H.; Linnebank, M.; Mooyer, P.; Huijmans,
J. G. M.; Mustonen, A.; Simola, K. O. J.; Arslan-Kirchner, M.; Battini,
R.; Briones, P.; Cardo, E.; Mandel, H.; Tschiedel, E.; Wanders, R.
J. A.; Koch, H. G.: Clinical, enzymatic, and molecular genetic characterization
of a biochemical variant type of argininosuccinic aciduria: prenatal
and postnatal diagnosis in 5 unrelated families. J. Inherit. Metab.
Dis. 25: 399-410, 2002.

4. Linnebank, M.; Tschiedel, E.; Haberle, J.; Linnebank, A.; Willenbring,
H.; Kleijer, W. J.; Koch, H. G.: Argininosuccinate lyase (ASL) deficiency:
mutation analysis in 27 patients and a completed structure of the
human ASL gene. Hum. Genet. 111: 350-359, 2002.

5. Matuo, S.; Tatsuno, M.; Kobayashi, K.; Saheki, T.; Miyata, T.;
Iwanaga, S.; Amaya, Y.; Mori, M.: Isolation of cDNA clones of human
argininosuccinate lyase and corrected amino acid sequence. FEBS Lett. 234:
395-399, 1988.

6. Nagamani, S. C. S.; Campeau, P. M.; Shchelochkov, O. A.; Premkumar,
M. H.; Guse, K.; Brunetti-Pierri, N.; Chen, Y.; Sun, Q.; Tang, Y.;
Palmer, D.; Reddy, A. K.; Li, L.; and 9 others: Nitric-oxide supplementation
for treatment of long-term complications in argininosuccinic aciduria. Am.
J. Hum. Genet. 90: 836-846, 2012.

7. Naylor, S. L.; Klebe, R. J.; Shows, T. B.: Argininosuccinic aciduria:
assignment of the argininosuccinate lyase gene to the pter-q22 region
of human chromosome 7 by bioautography. Proc. Nat. Acad. Sci. 75:
6159-6162, 1978.

8. O'Brien, W. E.; McInnes, R.; Kalumuck, K.; Adcock, M.: Cloning
and sequence analysis of cDNA for human argininosuccinate lyase. Proc.
Nat. Acad. Sci. 83: 7211-7215, 1986.

9. Piatigorsky, J.; O'Brien, W. E.; Norman, B. L.; Kalumuck, K.; Wistow,
G. J.; Borras, T.; Nickerson, J. M.; Wawrousek, E. F.: Gene sharing
by delta-crystallin and argininosuccinate lyase. Proc. Nat. Acad.
Sci. 85: 3479-3483, 1988.

10. Piatigorsky, J.; Wistow, G.: The recruitment of crystallins:
new functions precede gene duplication. Science 252: 1078-1079,
1991.

11. Todd, S.; McGill, J. R.; McCombs, J. L.; Moore, C. M.; Weider,
I.; Naylor, S. L.: cDNA sequence, interspecies comparison and gene
mapping analysis of argininosuccinate lyase. Genomics 4: 53-59,
1989.

12. Trevisson, E.; Salviati, L.; Baldoin, M. C.; Toldo, I.; Casarin,
A.; Sacconi, S.; Cesaro, L.; Basso, G.; Burlina, A. B.: Argininosuccinate
lyase deficiency: mutational spectrum in Italian patients and identification
of a novel ASL pseudogene. Hum. Mutat. 28: 694-702, 2007.

13. Walker, D. C.; McCloskey, D. A.; Simard, L. R.; McInnes, R. R.
: Molecular analysis of human argininosuccinate lyase (ASAL): mutant
characterization and alternate splicing of the active site. (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A227 only, 1989.

14. Walker, D. C.; McCloskey, D. A.; Simard, L. R.; McInnes, R. R.
: Molecular analysis of human argininosuccinate lyase: mutant characterization
and alternative splicing of the coding region. Proc. Nat. Acad. Sci. 87:
9625-9629, 1990.

15. Walker, D. C.; McCloskey, D. A.; Simard, L. R.; McInnes, R. R.
: Identification of a mutation frequently involved in interallelic
complementation at the human argininosuccinic acid lyase locus. (Abstract) Am.
J. Hum. Genet. 47 (suppl.): A169 only, 1990.

16. Zhao, S.; Xu, W.; Jiang, W.; Yu, W.; Lin, Y.; Zhang, T.; Yao,
J.; Zhou, L.; Zeng, Y.; Li, H.; Li, Y.; Shi, J.; and 10 others:
Regulation of cellular metabolism by protein lysine acetylation. Science 327:
1000-1004, 2010.

*FIELD* CN
Ada Hamosh - updated: 7/25/2012
Ada Hamosh - updated: 3/9/2010
Cassandra L. Kniffin - updated: 8/20/2007

*FIELD* CD
Cassandra L. Kniffin: 12/3/2003

*FIELD* ED
alopez: 08/01/2012
terry: 7/25/2012
alopez: 3/11/2010
terry: 3/9/2010
wwang: 9/5/2007
ckniffin: 8/20/2007
terry: 4/21/2005
carol: 12/4/2003
ckniffin: 12/3/2003