ARSA_HUMAN
ID ARSA_HUMAN Reviewed; 507 AA.
AC P15289; B2RCA6; B7XD04; F8WCC8; Q6ICI5; Q96CJ0;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 3.
DT 03-AUG-2022, entry version 231.
DE RecName: Full=Arylsulfatase A;
DE Short=ASA;
DE EC=3.1.6.8 {ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:24294900};
DE AltName: Full=Cerebroside-sulfatase;
DE Contains:
DE RecName: Full=Arylsulfatase A component B;
DE Contains:
DE RecName: Full=Arylsulfatase A component C;
DE Flags: Precursor;
GN Name=ARSA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2562955; DOI=10.1016/s0021-9258(19)85079-2;
RA Stein C., Gieselmann V., Kreysing J., Schmidt B., Pohlmann R., Waheed A.,
RA Meyer H.E., O'Brien J.S., von Figura K.;
RT "Cloning and expression of human arylsulfatase A.";
RL J. Biol. Chem. 264:1252-1259(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1975241; DOI=10.1111/j.1432-1033.1990.tb19167.x;
RA Kreysing J., von Figura K., Gieselmann V.;
RT "Structure of the arylsulfatase A gene.";
RL Eur. J. Biochem. 191:627-631(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=19262745;
RA Oshikawa M., Usami R., Kato S.;
RT "Characterization of the arylsulfatase I (ARSI) gene preferentially
RT expressed in the human retinal pigment epithelium cell line ARPE-19.";
RL Mol. Vis. 15:482-494(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP SER-391.
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-82; CYS-193; SER-350;
RP VAL-356; SER-391; SER-440 AND HIS-496.
RG NIEHS SNPs program;
RL Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
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., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., 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., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., 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., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT SER-391.
RC TISSUE=B-cell;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 19-33 AND 434-479, AND SUBUNIT.
RX PubMed=1352993; DOI=10.1016/0167-4838(92)90132-w;
RA Fujii T., Kobayashi T., Honke K., Gasa S., Ishikawa M., Shimizu T.,
RA Makita A.;
RT "Proteolytic processing of human lysosomal arylsulfatase A.";
RL Biochim. Biophys. Acta 1122:93-98(1992).
RN [10]
RP PARTIAL PROTEIN SEQUENCE, IDENTIFICATION BY MASS SPECTROMETRY, OXOALANINE
RP AT CYS-69, AND LACK OF OXOALANINE IN MSD.
RX PubMed=7628016; DOI=10.1016/0092-8674(95)90314-3;
RA Schmidt B., Selmer T., Ingendoh A., von Figura K.;
RT "A novel amino acid modification in sulfatases that is defective in
RT multiple sulfatase deficiency.";
RL Cell 82:271-278(1995).
RN [11]
RP OXOALANINE AT CYS-69, MUTAGENESIS OF CYS-69 AND 69-CYS-THR-70, AND
RP SUBCELLULAR LOCATION.
RX PubMed=9342345; DOI=10.1073/pnas.94.22.11963;
RA Dierks T., Schmidt B., von Figura K.;
RT "Conversion of cysteine to formylglycine: a protein modification in the
RT endoplasmic reticulum.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:11963-11968(1997).
RN [12]
RP INVOLVEMENT IN MSD.
RX PubMed=15146462; DOI=10.1002/humu.20040;
RA Cosma M.P., Pepe S., Parenti G., Settembre C., Annunziata I.,
RA Wade-Martins R., Domenico C.D., Natale P.D., Mankad A., Cox B., Uziel G.,
RA Mancini G.M., Zammarchi E., Donati M.A., Kleijer W.J., Filocamo M.,
RA Carrozzo R., Carella M., Ballabio A.;
RT "Molecular and functional analysis of SUMF1 mutations in multiple sulfatase
RT deficiency.";
RL Hum. Mutat. 23:576-581(2004).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-158 AND ASN-350.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [14]
RP CATALYTIC ACTIVITY, FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=24294900; DOI=10.1021/ac4023555;
RA Morena F., di Girolamo I., Emiliani C., Gritti A., Biffi A., Martino S.;
RT "A new analytical bench assay for the determination of arylsulfatase a
RT activity toward galactosyl-3-sulfate ceramide: implication for
RT metachromatic leukodystrophy diagnosis.";
RL Anal. Chem. 86:473-481(2014).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS), AND OLIGOMERIZATION.
RX PubMed=9521684; DOI=10.1021/bi9714924;
RA Lukatela G., Krauss N., Theis K., Selmer T., Gieselmann V., von Figura K.,
RA Saenger W.;
RT "Crystal structure of human arylsulfatase A: the aldehyde function and the
RT metal ion at the active site suggest a novel mechanism for sulfate ester
RT hydrolysis.";
RL Biochemistry 37:3654-3664(1998).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS), AND MUTAGENESIS OF CYS-69.
RX PubMed=11124905; DOI=10.1006/jmbi.2000.4297;
RA von Buelow R., Schmidt B., Dierks T., von Figura K., Uson I.;
RT "Crystal structure of an enzyme-substrate complex provides insight into the
RT interaction between human arylsulfatase A and its substrates during
RT catalysis.";
RL J. Mol. Biol. 305:269-277(2001).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 19-507, SUBUNIT, GLYCOSYLATION AT
RP ASN-158 AND ASN-184, ACTIVE SITE, ACTIVITY REGULATION, CALCIUM-BINDING, AND
RP COFACTOR.
RX PubMed=12888274; DOI=10.1016/s0162-0134(03)00176-4;
RA Chruszcz M., Laidler P., Monkiewicz M., Ortlund E., Lebioda L.,
RA Lewinski K.;
RT "Crystal structure of a covalent intermediate of endogenous human
RT arylsulfatase A.";
RL J. Inorg. Biochem. 96:386-392(2003).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 69-73 IN COMPLEX WITH SUMF1.
RX PubMed=16368756; DOI=10.1073/pnas.0507592102;
RA Roeser D., Preusser-Kunze A., Schmidt B., Gasow K., Wittmann J.G.,
RA Dierks T., von Figura K., Rudolph M.G.;
RT "A general binding mechanism for all human sulfatases by the formylglycine-
RT generating enzyme.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:81-86(2006).
RN [19]
RP REVIEW ON MLD VARIANTS.
RX PubMed=7866401; DOI=10.1002/humu.1380040402;
RA Gieselmann V., Zlotogora J., Harris A., Wenger D.A., Morris C.P.;
RT "Molecular genetics of metachromatic leukodystrophy.";
RL Hum. Mutat. 4:233-242(1994).
RN [20]
RP INVOLVEMENT IN MLD, VARIANT SER-350, AND CHARACTERIZATION OF VARIANT
RP SER-350.
RX PubMed=2574462; DOI=10.1073/pnas.86.23.9436;
RA Gieselmann V., Polten A., Kreysing J., von Figura K.;
RT "Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and
RT N-glycosylation site.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:9436-9440(1989).
RN [21]
RP VARIANT MLD ASP-99.
RX PubMed=1673291;
RA Kondo R., Wakamatsu N., Yoshino H., Fukuhara N., Miyatake T., Tsuji S.;
RT "Identification of a mutation in the arylsulfatase A gene of a patient with
RT adult-type metachromatic leukodystrophy.";
RL Am. J. Hum. Genet. 48:971-978(1991).
RN [22]
RP VARIANT MLD PHE-96.
RX PubMed=1678251;
RA Gieselmann V., Fluharty A.L., Toennesen T., von Figura K.;
RT "Mutations in the arylsulfatase A pseudodeficiency allele causing
RT metachromatic leukodystrophy.";
RL Am. J. Hum. Genet. 49:407-413(1991).
RN [23]
RP VARIANT MLD LEU-426, AND VARIANTS CYS-193 AND SER-391.
RX PubMed=1670590; DOI=10.1056/nejm199101033240104;
RA Polten A., Fluharty A.L., Fluharty C.B., Kappler J., von Figura K.,
RA Gieselmann V.;
RT "Molecular basis of different forms of metachromatic leukodystrophy.";
RL N. Engl. J. Med. 324:18-22(1991).
RN [24]
RP VARIANT MLD GLN-84.
RX PubMed=1353340; DOI=10.1002/ana.410310305;
RA Kappler J., von Figura K., Gieselmann V.;
RT "Late-onset metachromatic leukodystrophy: molecular pathology in two
RT siblings.";
RL Ann. Neurol. 31:256-261(1992).
RN [25]
RP VARIANT MLD SER-309.
RX PubMed=8101038;
RA Kreysing J., Bohne W., Bosenberg C., Marchesini S., Turpin J.C.,
RA Baumann N., von Figura K., Gieselmann V.;
RT "High residual arylsulfatase A (ARSA) activity in a patient with late-
RT infantile metachromatic leukodystrophy.";
RL Am. J. Hum. Genet. 53:339-346(1993).
RN [26]
RP VARIANT MLD ARG-245.
RX PubMed=8101083; DOI=10.1089/dna.1993.12.493;
RA Hasegawa Y., Kawame H., Eto Y.;
RT "Mutations in the arylsulfatase A gene of Japanese patients with
RT metachromatic leukodystrophy.";
RL DNA Cell Biol. 12:493-498(1993).
RN [27]
RP VARIANT MLD LEU-426.
RX PubMed=8095918; DOI=10.1007/bf00230227;
RA Barth M.L., Fensom A., Harris A.;
RT "Prevalence of common mutations in the arylsulphatase A gene in
RT metachromatic leukodystrophy patients diagnosed in Britain.";
RL Hum. Genet. 91:73-77(1993).
RN [28]
RP VARIANT MLD SER-122.
RX PubMed=7902317; DOI=10.1007/bf00216449;
RA Honke K., Kobayashi T., Fujii T., Gasa S., Xu M., Takamaru Y., Kondo R.,
RA Tsuji S., Makita A.;
RT "An adult-type metachromatic leukodystrophy caused by substitution of
RT serine for glycine-122 in arylsulfatase A.";
RL Hum. Genet. 92:451-456(1993).
RN [29]
RP VARIANTS MLD VAL-212; VAL-224 AND TYR-295.
RX PubMed=7906588; DOI=10.1093/hmg/2.12.2117;
RA Barth M.L., Fensom A., Harris A.;
RT "Missense mutations in the arylsulphatase A genes of metachromatic
RT leukodystrophy patients.";
RL Hum. Mol. Genet. 2:2117-2121(1993).
RN [30]
RP VARIANT MLD MET-274.
RX PubMed=8104633; DOI=10.1002/humu.1380020405;
RA Harvey J.S., Nelson P.V., Carey W.F., Robertson E.F., Morris C.P.;
RT "An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile
RT metachromatic leukodystrophy.";
RL Hum. Mutat. 2:261-267(1993).
RN [31]
RP VARIANT MLD ILE-409.
RX PubMed=7909527; DOI=10.1007/bf00201666;
RA Hasegawa Y., Kawame H., Ida H., Ohashi T., Eto Y.;
RT "Single exon mutation in arylsulfatase A gene has two effects: loss of
RT enzyme activity and aberrant splicing.";
RL Hum. Genet. 93:415-420(1994).
RN [32]
RP VARIANTS MLD ASP-86; LEU-96; HIS-190; MET-274 AND TRP-370, AND
RP CHARACTERIZATION OF VARIANTS MLD ASP-86; LEU-96; HIS-190; MET-274 AND
RP TRP-370.
RX PubMed=7825603;
RA Heinisch U., Zlotogora J., Kafert S., Gieselmann V.;
RT "Multiple mutations are responsible for the high frequency of metachromatic
RT leukodystrophy in a small geographic area.";
RL Am. J. Hum. Genet. 56:51-57(1995).
RN [33]
RP VARIANT MLD LEU-136.
RX PubMed=7860068; DOI=10.1007/bf00209402;
RA Kafert S., Heinisch U., Zlotogora J., Gieselmann V.;
RT "A missense mutation P136L in the arylsulfatase A gene causes instability
RT and loss of activity of the mutant enzyme.";
RL Hum. Genet. 95:201-204(1995).
RN [34]
RP VARIANTS MLD LEU-82; TYR-172; CYS-201; GLN-311; VAL-335 AND TRP-390.
RX PubMed=7581401; DOI=10.1002/humu.1380060210;
RA Barth M.L., Fensom A., Harris A.;
RT "Identification of seven novel mutations associated with metachromatic
RT leukodystrophy.";
RL Hum. Mutat. 6:170-176(1995).
RN [35]
RP VARIANTS MLD HIS-153 AND VAL-308, AND CHARACTERIZATION OF VARIANTS MLD
RP HIS-153 AND VAL-308.
RX PubMed=8891236; DOI=10.1016/0387-7604(96)00041-1;
RA Tsuda T., Hasegawa Y., Eto Y.;
RT "Two novel mutations in a Japanese patient with the late-infantile form of
RT metachromatic leukodystrophy.";
RL Brain Dev. 18:400-403(1996).
RN [36]
RP CHARACTERIZATION OF VARIANTS MET-274 AND VAL-335.
RX PubMed=8723680;
RX DOI=10.1002/(sici)1098-1004(1996)7:4<311::aid-humu4>3.0.co;2-b;
RA Hess B., Kafert S., Heinisch U., Wenger D.A., Zlotogora J., Gieselmann V.;
RT "Characterization of two arylsulfatase A missense mutations D335V and T274M
RT causing late infantile metachromatic leukodystrophy.";
RL Hum. Mutat. 7:311-317(1996).
RN [37]
RP VARIANT MLD PRO-428.
RX PubMed=9272717; DOI=10.1111/j.1399-0004.1997.tb02518.x;
RA Regis S., Filocamo M., Stroppiano M., Corsolini F., Gatti R.;
RT "A T > C transition causing a Leu > Pro substitution in a conserved region
RT of the arylsulfatase A gene in a late infantile metachromatic
RT leukodystrophy patient.";
RL Clin. Genet. 52:65-67(1997).
RN [38]
RP VARIANTS MLD ASN-95; ARG-119; TYR-152; HIS-244; TYR-250; THR-314; ASN-367
RP AND CYS-384, AND VARIANT HIS-496.
RX PubMed=9090526;
RX DOI=10.1002/(sici)1098-1004(1997)9:3<234::aid-humu4>3.0.co;2-7;
RA Draghia R., Letourneur F., Drugan C., Manicom J., Blanchot C., Kahn A.,
RA Poenaru L., Caillaud C.;
RT "Metachromatic leukodystrophy: identification of the first deletion in exon
RT 1 and of nine novel point mutations in the arylsulfatase A gene.";
RL Hum. Mutat. 9:234-242(1997).
RN [39]
RP VARIANT MLD 406-SER--THR-408 DEL.
RX PubMed=9490297; DOI=10.1007/s004390050652;
RA Regis S., Filocamo M., Stroppiano M., Corsolini F., Caroli F., Gatti R.;
RT "A 9-bp deletion (2320del9) on the background of the arylsulfatase A
RT pseudodeficiency allele in a metachromatic leukodystrophy patient and in a
RT patient with nonprogressive neurological symptoms.";
RL Hum. Genet. 102:50-53(1998).
RN [40]
RP VARIANTS MLD PRO-135 AND SER-179.
RX PubMed=9600244; DOI=10.1007/s004390050721;
RA Gomez-Lira M., Perusi C., Mottes M., Pignatti P.F., Manfredi M.,
RA Rizzuto N., Salviati A.;
RT "Molecular genetic characterization of two metachromatic leukodystrophy
RT patients who carry the T799G mutation and show different phenotypes;
RT description of a novel null-type mutation.";
RL Hum. Genet. 102:459-463(1998).
RN [41]
RP ERRATUM OF PUBMED:9600244.
RA Gomez-Lira M., Perusi C., Mottes M., Pignatti P.F., Manfredi M.,
RA Rizzuto N., Salviati A.;
RL Hum. Genet. 102:602-602(1998).
RN [42]
RP VARIANT HIS-496.
RX PubMed=9744473;
RX DOI=10.1002/(sici)1098-1004(1998)12:4<238::aid-humu3>3.0.co;2-b;
RA Ricketts M.H., Poretz R.D., Manowitz P.;
RT "The R496H mutation of arylsulfatase A does not cause metachromatic
RT leukodystrophy.";
RL Hum. Mutat. 12:238-239(1998).
RN [43]
RP VARIANTS MLD GLN-390 AND TYR-397.
RX PubMed=9452102; DOI=10.1002/humu.1380110181;
RA Coulter-Mackie M.B., Gagnier L.;
RT "Two novel mutations in the arylsulfatase A gene associated with juvenile
RT (R390Q) and adult onset (H397Y) metachromatic leukodystrophy.";
RL Hum. Mutat. Suppl. 1:S254-S256(1998).
RN [44]
RP VARIANT MLD SER-298, AND CHARACTERIZATION OF VARIANT MLD SER-298.
RX PubMed=9819708; DOI=10.1023/a:1005405418215;
RA Kurosawa K., Ida H., Eto Y.;
RT "Prevalence of arylsulphatase A mutations in 11 Japanese patients with
RT metachromatic leukodystrophy: identification of two novel mutations.";
RL J. Inherit. Metab. Dis. 21:781-782(1998).
RN [45]
RP VARIANTS PRO-76; CYS-193; SER-391 AND VAL-464.
RX PubMed=9888390;
RX DOI=10.1002/(sici)1098-1004(1999)13:1<61::aid-humu7>3.0.co;2-h;
RA Berger J., Gmach M., Mayr U., Molzer B., Bernheimer H.;
RT "Coincidence of two novel arylsulfatase A alleles and mutation 459+1G>A
RT within a family with metachromatic leukodystrophy: molecular basis of
RT phenotypic heterogeneity.";
RL Hum. Mutat. 13:61-68(1999).
RN [46]
RP VARIANTS MLD PHE-300 AND THR-425.
RX PubMed=10220151;
RX DOI=10.1002/(sici)1098-1004(1999)13:4<337::aid-humu14>3.0.co;2-9;
RA Marcao A., Amaral O., Pinto E., Pinto R., Sa Miranda M.C.;
RT "Metachromatic leucodystrophy in Portugal-finding of four new molecular
RT lesions: C300F, P425T, g.1190-1191insC, and g.2408delC.";
RL Hum. Mutat. 13:337-338(1999).
RN [47]
RP VARIANTS MLD SER-32; PRO-68; TRP-84; ALA-94; VAL-99; SER-136; VAL-212;
RP TYR-227; HIS-255; HIS-288; ASP-308; ILE-327 AND LEU-377, AND VARIANTS
RP CYS-193; SER-350 AND SER-391.
RX PubMed=10477432;
RX DOI=10.1002/(sici)1098-1004(1999)14:3<240::aid-humu7>3.0.co;2-l;
RA Gort L., Coll M.J., Chabas A.;
RT "Identification of 12 novel mutations and two new polymorphisms in the
RT arylsulfatase A gene: haplotype and genotype-phenotype correlation studies
RT in Spanish metachromatic leukodystrophy patients.";
RL Hum. Mutat. 14:240-248(1999).
RN [48]
RP VARIANTS MLD SER-179 AND TYR-281.
RX PubMed=10533072;
RX DOI=10.1002/(sici)1098-1004(199911)14:5<447::aid-humu12>3.0.co;2-1;
RA Halsall D.J., Halligan E.P., Elsey T.S., Cox T.M.;
RT "Metachromatic leucodystrophy: a newly identified mutation in
RT arylsulphatase A, D281Y, found as a compound heterozygote with I179L in an
RT adult onset case.";
RL Hum. Mutat. 14:447-447(1999).
RN [49]
RP VARIANTS MLD LEU-148; THR-191; VAL-335; TYR-397 AND LEU-426.
RX PubMed=10381328; DOI=10.1006/mgme.1999.2865;
RA Qu Y., Shapira E., Desnick R.J.;
RT "Metachromatic leukodystrophy: subtype genotype/phenotype correlations and
RT identification of novel missense mutations (P148L and P191T) causing the
RT juvenile-onset disease.";
RL Mol. Genet. Metab. 67:206-212(1999).
RN [50]
RP VARIANTS MLD ASP-86; CYS-201; HIS-255 AND ASP-312, CHARACTERIZATION OF
RP VARIANTS MLD ASP-86; CYS-201; HIS-255 AND ASP-312, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=10751093;
RX DOI=10.1002/(sici)1096-8628(20000306)91:1<68::aid-ajmg13>3.0.co;2-g;
RA Hermann S., Schestag F., Polten A., Kafert S., Penzien J., Zlotogora J.,
RA Baumann N., Gieselmann V.;
RT "Characterization of four arylsulfatase A missense mutations G86D, Y201C,
RT D255H, and E312D causing metachromatic leukodystrophy.";
RL Am. J. Med. Genet. 91:68-73(2000).
RN [51]
RP VARIANT MLD PRO-286, AND VARIANT SER-391.
RX PubMed=11061266; DOI=10.1212/wnl.55.7.1036;
RA Felice K.J., Gomez Lira M., Natowicz M., Grunnet M.L., Tsongalis G.J.,
RA Sima A.A.F., Kaplan R.F.;
RT "Adult-onset MLD: a gene mutation with isolated polyneuropathy.";
RL Neurology 55:1036-1039(2000).
RN [52]
RP VARIANT MLD GLY-143, AND CHARACTERIZATION OF VARIANT MLD GLY-143.
RX PubMed=11020646; DOI=10.1016/s0887-8994(00)00164-8;
RA Arbour L.T., Silver K., Hechtman P., Treacy E.P., Coulter-Mackie M.B.;
RT "Variable onset of metachromatic leukodystrophy in a Vietnamese family.";
RL Pediatr. Neurol. 23:173-176(2000).
RN [53]
RP VARIANT MLD ILE-408, AND VARIANTS CYS-193 AND SER-391.
RX PubMed=11456299; DOI=10.1002/ana.1076;
RA Comabella M., Waye J.S., Raguer N., Eng B., Dominguez C., Navarro C.,
RA Borras C., Krivit W., Montalban X.;
RT "Late-onset metachromatic leukodystrophy clinically presenting as isolated
RT peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation
RT and a newly identified missense mutation (Thr408Ile) in a Spanish family.";
RL Ann. Neurol. 50:108-112(2001).
RN [54]
RP VARIANT MLD LYS-253, CHARACTERIZATION OF VARIANT MLD LYS-253, AND
RP CHARACTERIZATION OF VARIANTS SER-350; SER-391 AND LEU-426.
RX PubMed=11941485; DOI=10.1007/s00439-002-0701-y;
RA Regis S., Corsolini F., Stroppiano M., Cusano R., Filocamo M.;
RT "Contribution of arylsulfatase A mutations located on the same allele to
RT enzyme activity reduction and metachromatic leukodystrophy severity.";
RL Hum. Genet. 110:351-355(2002).
RN [55]
RP CHARACTERIZATION OF VARIANTS MLD PHE-300 AND THR-425.
RX PubMed=12503099; DOI=10.1002/ajmg.a.10822;
RA Marcao A., Simonis H., Schestag F., Sa Miranda M.C., Gieselmann V.;
RT "Biochemical characterization of two (C300F, P425T) arylsulfatase A
RT missense mutations.";
RL Am. J. Med. Genet. A 116:238-242(2003).
RN [56]
RP CHARACTERIZATION OF VARIANTS MLD PHE-300 AND THR-425.
RX PubMed=12788103; DOI=10.1016/s0006-291x(03)00969-0;
RA Marcao A., Azevedo J.E., Gieselmann V., Sa Miranda M.C.;
RT "Oligomerization capacity of two arylsulfatase A mutants: C300F and
RT P425T.";
RL Biochem. Biophys. Res. Commun. 306:293-297(2003).
RN [57]
RP VARIANTS MLD LEU-155; GLN-181; VAL-212; HIS-306; SER-325; VAL-335; LEU-426
RP AND SER-429.
RX PubMed=14517960; DOI=10.1002/humu.9190;
RA Eng B., Nakamura L.N., O'Reilly N., Schokman N., Nowaczyk M.M.J.,
RA Krivit W., Waye J.S.;
RT "Identification of nine novel arylsulfatase A (ARSA) gene mutations in
RT patients with metachromatic leukodystrophy (MLD).";
RL Hum. Mutat. 22:418-419(2003).
RN [58]
RP VARIANTS MLD SER-136; SER-247; GLU-381 LEU-426 AND GLY-469.
RX PubMed=14680985; DOI=10.1016/j.ymgme.2003.08.004;
RA Olkhovich N.V., Takamura N., Pichkur N.A., Gorovenko N.G., Aoyagi K.,
RA Yamashita S.;
RT "Novel mutations in arylsulfatase A gene in three Ukrainian families with
RT metachromatic leukodystrophy.";
RL Mol. Genet. Metab. 80:360-363(2003).
RN [59]
RP VARIANTS MLD ASN-29; ARG-156; SER-179; SER-293; TYR-294; SER-309 AND
RP LEU-426, VARIANTS CYS-193 AND SER-391, AND CHARACTERIZATION OF VARIANTS MLD
RP ASN-29; ARG-156; SER-293 AND TYR-294.
RX PubMed=15326627; DOI=10.1002/ajmg.a.30118;
RA Berna L., Gieselmann V., Poupetova H., Hrebicek M., Elleder M.,
RA Ledvinova J.;
RT "Novel mutations associated with metachromatic leukodystrophy: phenotype
RT and expression studies in nine Czech and Slovak patients.";
RL Am. J. Med. Genet. A 129:277-281(2004).
RN [60]
RP VARIANTS MLD ASP-293 AND GLY-489, AND VARIANT SER-350.
RX PubMed=15026521; DOI=10.1136/jnnp.2003.017400;
RA Gallo S., Randi D., Bertelli M., Salviati A., Pandolfo M.;
RT "Late onset MLD with normal nerve conduction associated with two novel
RT missense mutations in the ASA gene.";
RL J. Neurol. Neurosurg. Psych. 75:655-657(2004).
RN [61]
RP VARIANT MLD VAL-219, AND CHARACTERIZATION OF VARIANT MLD VAL-219.
RX PubMed=15710861; DOI=10.1001/archneur.62.2.309;
RA Marcao A.M., Wiest R., Schindler K., Wiesmann U., Weis J., Schroth G.,
RA Miranda M.C.S., Sturzenegger M., Gieselmann V.;
RT "Adult onset metachromatic leukodystrophy without electroclinical
RT peripheral nervous system involvement: a new mutation in the ARSA gene.";
RL Arch. Neurol. 62:309-313(2005).
RN [62]
RP VARIANTS MLD ASP-18; HIS-30; GLN-84; PRO-137 DEL; ASP-154; SER-179;
RP CYS-201; PRO-212; HIS-217; LYS-253; SER-282; ASN-302; TRP-370; ASN-376;
RP TRP-390 AND PRO-428, AND CHARACTERIZATION OF VARIANTS MLD ASP-18; HIS-30;
RP PRO-212; HIS-217; SER-282; ASN-302; TRP-370 AND ASN-376.
RX PubMed=18693274; DOI=10.1002/humu.20851;
RA Grossi S., Regis S., Rosano C., Corsolini F., Uziel G., Sessa M.,
RA Di Rocco M., Parenti G., Deodato F., Leuzzi V., Biancheri R., Filocamo M.;
RT "Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients
RT with metachromatic leukodystrophy: identification and functional
RT characterization of 11 novel ARSA alleles.";
RL Hum. Mutat. 29:E220-E230(2008).
RN [63]
RP VARIANTS MLD PRO-52; ASP-138; PRO-212; MET-304; LYS-307 AND GLY-406, AND
RP CHARACTERIZATION OF VARIANTS MLD PRO-52; ASP-138; PRO-212; MET-304; LYS-307
RP AND GLY-406.
RX PubMed=19606494; DOI=10.1002/humu.21093;
RA Cesani M., Capotondo A., Plati T., Sergi L.S., Fumagalli F.,
RA Roncarolo M.G., Naldini L., Comi G., Sessa M., Biffi A.;
RT "Characterization of new arylsulfatase A gene mutations reinforces
RT genotype-phenotype correlation in metachromatic leukodystrophy.";
RL Hum. Mutat. 30:E936-E945(2009).
RN [64]
RP VARIANTS MLD SER-179; SER-247; CYS-288; VAL-335; LYS-382; GLN-390; TRP-390;
RP TYR-397 AND LEU-426.
RX PubMed=20339381; DOI=10.1038/jhg.2010.25;
RA Lugowska A., Ploski R., Wlodarski P., Tylki-Szymanska A.;
RT "Molecular bases of metachromatic leukodystrophy in Polish patients.";
RL J. Hum. Genet. 55:394-396(2010).
RN [65]
RP VARIANTS MLD ASP-99 AND ILE-409.
RX PubMed=21265945; DOI=10.1111/j.1440-1819.2010.02169.x;
RA Hayashi T., Nakamura M., Ichiba M., Matsuda M., Kato M., Shiokawa N.,
RA Shimo H., Tomiyasu A., Mori S., Tomiyasu Y., Ishizuka T., Inamori Y.,
RA Okamoto Y., Umehara F., Arimura K., Nakabeppu Y., Sano A.;
RT "Adult-type metachromatic leukodystrophy with compound heterozygous ARSA
RT mutations: a case report and phenotypic comparison with a previously
RT reported case.";
RL Psychiatry Clin. Neurosci. 65:105-108(2011).
CC -!- FUNCTION: Hydrolyzes cerebroside sulfate. {ECO:0000269|PubMed:10751093,
CC ECO:0000269|PubMed:24294900}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-acyl-1-beta-D-(3-O-sulfo)-galactosyl-sphing-4-enine =
CC a beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine + H(+) + sulfate;
CC Xref=Rhea:RHEA:21300, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16189, ChEBI:CHEBI:18390, ChEBI:CHEBI:75956; EC=3.1.6.8;
CC Evidence={ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:24294900};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21301;
CC Evidence={ECO:0000269|PubMed:24294900};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:12888274};
CC Note=Binds 1 Ca(2+) ion per subunit. {ECO:0000269|PubMed:12888274};
CC -!- ACTIVITY REGULATION: Inhibited by phosphate. The phosphate forms a
CC covalent bond with the active site 3-oxoalanine.
CC {ECO:0000269|PubMed:12888274}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.099 mM for galactosyl-3-sulfate ceramide
CC {ECO:0000269|PubMed:24294900};
CC Note=kcat is 0,087 sec(-1) with galactosyl-3-sulfate ceramide as
CC substrate. {ECO:0000269|PubMed:24294900};
CC pH dependence:
CC Optimum pH is 4.5. {ECO:0000269|PubMed:24294900};
CC -!- SUBUNIT: Homodimer at neutral pH and homooctamer at acidic pH. Exists
CC both as a single chain of 58 kDa (component A) or as a chain of 50 kDa
CC (component B) linked by disulfide bond(s) to a 7 kDa chain (component
CC C). Interacts with SUMF1. {ECO:0000269|PubMed:12888274,
CC ECO:0000269|PubMed:1352993, ECO:0000269|PubMed:16368756}.
CC -!- INTERACTION:
CC P15289; P50995: ANXA11; NbExp=3; IntAct=EBI-2117357, EBI-715243;
CC P15289; Q6P5X5: C22orf39; NbExp=3; IntAct=EBI-2117357, EBI-7317823;
CC P15289; Q13554-3: CAMK2B; NbExp=3; IntAct=EBI-2117357, EBI-11523526;
CC P15289; O60826: CCDC22; NbExp=3; IntAct=EBI-2117357, EBI-3943153;
CC P15289; Q96D98: EID2B; NbExp=3; IntAct=EBI-2117357, EBI-724968;
CC P15289; Q9H0I2: ENKD1; NbExp=3; IntAct=EBI-2117357, EBI-744099;
CC P15289; Q12951-2: FOXI1; NbExp=3; IntAct=EBI-2117357, EBI-12018822;
CC P15289; Q16512: PKN1; NbExp=3; IntAct=EBI-2117357, EBI-602382;
CC P15289; P28069: POU1F1; NbExp=3; IntAct=EBI-2117357, EBI-8673859;
CC P15289; O75360: PROP1; NbExp=3; IntAct=EBI-2117357, EBI-9027467;
CC P15289; Q9BQY4: RHOXF2; NbExp=3; IntAct=EBI-2117357, EBI-372094;
CC P15289; Q15645: TRIP13; NbExp=13; IntAct=EBI-2117357, EBI-358993;
CC P15289; O95231: VENTX; NbExp=3; IntAct=EBI-2117357, EBI-10191303;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC {ECO:0000269|PubMed:9342345}. Lysosome {ECO:0000305|PubMed:2562955}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P15289-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P15289-2; Sequence=VSP_046190;
CC -!- PTM: The conversion to 3-oxoalanine (also known as C-formylglycine,
CC FGly), of a serine or cysteine residue in prokaryotes and of a cysteine
CC residue in eukaryotes, is critical for catalytic activity. This post-
CC translational modification is severely defective in multiple sulfatase
CC deficiency (MSD). {ECO:0000269|PubMed:7628016,
CC ECO:0000269|PubMed:9342345}.
CC -!- DISEASE: Metachromatic leukodystrophy (MLD) [MIM:250100]: An autosomal
CC recessive disease caused by abnormal intralysosomal accumulation of
CC cerebroside-3-sulfate in central and peripheral nervous systems, as
CC well as other organs. MLD is clinically characterized by
CC leukodystrophy, progressive demyelination and a variety of neurological
CC symptoms, including gait disturbances, ataxias, optical atrophy,
CC dementia, seizures, and spastic tetraparesis. Decreased arylsulfatase A
CC activity is detected in urine, leukocytes, and fibroblasts of affected
CC individuals. Several forms of the disease can be distinguished
CC according to the age at onset and disease severity: late infantile,
CC juvenile and adult forms, partial cerebroside sulfate deficiency, and
CC pseudoarylsulfatase A deficiency. Individuals with pseudoarylsulfatase
CC A deficiency have low arylsulfatase A activity but lack neurological
CC manifestations and are apparently healthy.
CC {ECO:0000269|PubMed:10220151, ECO:0000269|PubMed:10381328,
CC ECO:0000269|PubMed:10477432, ECO:0000269|PubMed:10533072,
CC ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:11020646,
CC ECO:0000269|PubMed:11061266, ECO:0000269|PubMed:11456299,
CC ECO:0000269|PubMed:11941485, ECO:0000269|PubMed:12503099,
CC ECO:0000269|PubMed:12788103, ECO:0000269|PubMed:1353340,
CC ECO:0000269|PubMed:14517960, ECO:0000269|PubMed:14680985,
CC ECO:0000269|PubMed:15026521, ECO:0000269|PubMed:15326627,
CC ECO:0000269|PubMed:15710861, ECO:0000269|PubMed:1670590,
CC ECO:0000269|PubMed:1673291, ECO:0000269|PubMed:1678251,
CC ECO:0000269|PubMed:18693274, ECO:0000269|PubMed:19606494,
CC ECO:0000269|PubMed:20339381, ECO:0000269|PubMed:21265945,
CC ECO:0000269|PubMed:2574462, ECO:0000269|PubMed:7581401,
CC ECO:0000269|PubMed:7825603, ECO:0000269|PubMed:7860068,
CC ECO:0000269|PubMed:7902317, ECO:0000269|PubMed:7906588,
CC ECO:0000269|PubMed:7909527, ECO:0000269|PubMed:8095918,
CC ECO:0000269|PubMed:8101038, ECO:0000269|PubMed:8101083,
CC ECO:0000269|PubMed:8104633, ECO:0000269|PubMed:8891236,
CC ECO:0000269|PubMed:9090526, ECO:0000269|PubMed:9272717,
CC ECO:0000269|PubMed:9452102, ECO:0000269|PubMed:9490297,
CC ECO:0000269|PubMed:9600244, ECO:0000269|PubMed:9819708}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Multiple sulfatase deficiency (MSD) [MIM:272200]: A clinically
CC and biochemically heterogeneous disorder caused by the simultaneous
CC impairment of all sulfatases, due to defective post-translational
CC modification and activation. It combines features of individual
CC sulfatase deficiencies such as metachromatic leukodystrophy,
CC mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus,
CC ichthyosis, neurologic deterioration and developmental delay.
CC {ECO:0000269|PubMed:15146462}. Note=The protein represented in this
CC entry is involved in disease pathogenesis. Arylsulfatase A activity is
CC impaired in multiple sulfatase deficiency due to mutations in SUMF1
CC (PubMed:15146462). SUMF1 mutations result in defective post-
CC translational modification of ARSA at residue Cys-69 that is not
CC converted to 3-oxoalanine (PubMed:7628016).
CC {ECO:0000269|PubMed:15146462, ECO:0000269|PubMed:7628016}.
CC -!- MISCELLANEOUS: The metal cofactor was first identified as magnesium
CC ion, based on the structure of the recombinant protein, but when
CC purified from human placenta, the protein contains 1 calcium ion per
CC subunit.
CC -!- SIMILARITY: Belongs to the sulfatase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB03341.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAH11167.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/arsa/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Arylsulfatase A entry;
CC URL="https://en.wikipedia.org/wiki/Arylsulfatase_A";
CC -!- WEB RESOURCE: Name=Arylsulfatase A (ARSA); Note=Leiden Open Variation
CC Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/ARSA";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; X52151; CAA36399.1; -; mRNA.
DR EMBL; X52150; CAA36398.1; -; Genomic_DNA.
DR EMBL; AB448736; BAH11167.1; ALT_INIT; mRNA.
DR EMBL; CR456383; CAG30269.1; -; mRNA.
DR EMBL; AK098659; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK315011; BAG37503.1; -; mRNA.
DR EMBL; AY271820; AAP03431.1; -; Genomic_DNA.
DR EMBL; U62317; AAB03341.1; ALT_INIT; Genomic_DNA.
DR EMBL; BC014210; AAH14210.2; -; mRNA.
DR CCDS; CCDS46736.1; -. [P15289-2]
DR PIR; S11031; KJHUAA.
DR RefSeq; NP_000478.3; NM_000487.5.
DR RefSeq; NP_001078894.2; NM_001085425.2.
DR RefSeq; NP_001078895.2; NM_001085426.2.
DR RefSeq; NP_001078896.2; NM_001085427.2.
DR RefSeq; NP_001078897.1; NM_001085428.2. [P15289-2]
DR RefSeq; XP_011528992.1; XM_011530690.2.
DR PDB; 1AUK; X-ray; 2.10 A; A=19-507.
DR PDB; 1E1Z; X-ray; 2.40 A; P=19-507.
DR PDB; 1E2S; X-ray; 2.35 A; P=19-507.
DR PDB; 1E33; X-ray; 2.50 A; P=19-507.
DR PDB; 1E3C; X-ray; 2.65 A; P=19-507.
DR PDB; 1N2K; X-ray; 2.75 A; A=19-507.
DR PDB; 1N2L; X-ray; 3.20 A; A=19-507.
DR PDB; 2AIJ; X-ray; 1.55 A; P=69-73.
DR PDB; 2AIK; X-ray; 1.73 A; P=68-74.
DR PDB; 2HI8; X-ray; 1.64 A; P=69-73.
DR PDBsum; 1AUK; -.
DR PDBsum; 1E1Z; -.
DR PDBsum; 1E2S; -.
DR PDBsum; 1E33; -.
DR PDBsum; 1E3C; -.
DR PDBsum; 1N2K; -.
DR PDBsum; 1N2L; -.
DR PDBsum; 2AIJ; -.
DR PDBsum; 2AIK; -.
DR PDBsum; 2HI8; -.
DR AlphaFoldDB; P15289; -.
DR SMR; P15289; -.
DR BioGRID; 106903; 87.
DR IntAct; P15289; 32.
DR MINT; P15289; -.
DR STRING; 9606.ENSP00000216124; -.
DR ChEMBL; CHEMBL2193; -.
DR DrugBank; DB03821; 2-Amino-3-Hydroxy-3-Phosphonooxy-Propionic Acid.
DR DrugBank; DB01800; 4-Nitrocatechol sulfate.
DR DrugBank; DB01141; Micafungin.
DR DrugBank; DB04786; Suramin.
DR SwissLipids; SLP:000000913; -.
DR GlyConnect; 61; 11 N-Linked glycans.
DR GlyGen; P15289; 4 sites, 27 N-linked glycans (4 sites).
DR iPTMnet; P15289; -.
DR PhosphoSitePlus; P15289; -.
DR BioMuta; ARSA; -.
DR EPD; P15289; -.
DR jPOST; P15289; -.
DR MassIVE; P15289; -.
DR MaxQB; P15289; -.
DR PaxDb; P15289; -.
DR PeptideAtlas; P15289; -.
DR PRIDE; P15289; -.
DR ProteomicsDB; 31108; -.
DR ProteomicsDB; 53123; -. [P15289-1]
DR Antibodypedia; 215; 490 antibodies from 36 providers.
DR DNASU; 410; -.
DR Ensembl; ENST00000453344.6; ENSP00000412542.2; ENSG00000100299.18. [P15289-2]
DR GeneID; 410; -.
DR KEGG; hsa:410; -.
DR UCSC; uc003bmz.6; human. [P15289-1]
DR CTD; 410; -.
DR DisGeNET; 410; -.
DR GeneCards; ARSA; -.
DR GeneReviews; ARSA; -.
DR HGNC; HGNC:713; ARSA.
DR HPA; ENSG00000100299; Low tissue specificity.
DR MalaCards; ARSA; -.
DR MIM; 250100; phenotype.
DR MIM; 272200; phenotype.
DR MIM; 607574; gene.
DR neXtProt; NX_P15289; -.
DR OpenTargets; ENSG00000100299; -.
DR Orphanet; 309271; Metachromatic leukodystrophy, adult form.
DR Orphanet; 309263; Metachromatic leukodystrophy, juvenile form.
DR Orphanet; 309256; Metachromatic leukodystrophy, late infantile form.
DR Orphanet; 751; NON RARE IN EUROPE: Pseudoarylsulfatase A deficiency.
DR PharmGKB; PA25005; -.
DR VEuPathDB; HostDB:ENSG00000100299; -.
DR eggNOG; KOG3867; Eukaryota.
DR GeneTree; ENSGT00940000157610; -.
DR InParanoid; P15289; -.
DR OrthoDB; 515367at2759; -.
DR PhylomeDB; P15289; -.
DR BioCyc; MetaCyc:HS02032-MON; -.
DR PathwayCommons; P15289; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR Reactome; R-HSA-1663150; The activation of arylsulfatases.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SABIO-RK; P15289; -.
DR SignaLink; P15289; -.
DR SIGNOR; P15289; -.
DR BioGRID-ORCS; 410; 35 hits in 1084 CRISPR screens.
DR ChiTaRS; ARSA; human.
DR EvolutionaryTrace; P15289; -.
DR GeneWiki; Arylsulfatase_A; -.
DR GenomeRNAi; 410; -.
DR Pharos; P15289; Tbio.
DR PRO; PR:P15289; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; P15289; protein.
DR Bgee; ENSG00000100299; Expressed in right uterine tube and 101 other tissues.
DR ExpressionAtlas; P15289; baseline and differential.
DR Genevisible; P15289; HS.
DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0005764; C:lysosome; TAS:ProtInc.
DR GO; GO:0004065; F:arylsulfatase activity; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0004098; F:cerebroside-sulfatase activity; IEA:UniProtKB-EC.
DR GO; GO:0008484; F:sulfuric ester hydrolase activity; IDA:MGI.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR Gene3D; 3.40.720.10; -; 1.
DR InterPro; IPR017850; Alkaline_phosphatase_core_sf.
DR InterPro; IPR024607; Sulfatase_CS.
DR InterPro; IPR000917; Sulfatase_N.
DR Pfam; PF00884; Sulfatase; 1.
DR SUPFAM; SSF53649; SSF53649; 1.
DR PROSITE; PS00523; SULFATASE_1; 1.
DR PROSITE; PS00149; SULFATASE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Direct protein sequencing;
KW Disease variant; Disulfide bond; Endoplasmic reticulum; Glycoprotein;
KW Hydrolase; Ichthyosis; Leukodystrophy; Lipid metabolism; Lysosome;
KW Metachromatic leukodystrophy; Metal-binding; Reference proteome; Signal.
FT SIGNAL 1..18
FT /evidence="ECO:0000269|PubMed:1352993"
FT CHAIN 19..507
FT /note="Arylsulfatase A"
FT /id="PRO_0000033417"
FT CHAIN 19..444
FT /note="Arylsulfatase A component B"
FT /id="PRO_0000033418"
FT CHAIN 448..507
FT /note="Arylsulfatase A component C"
FT /id="PRO_0000033419"
FT ACT_SITE 69
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:7628016"
FT ACT_SITE 125
FT /evidence="ECO:0000269|PubMed:12888274"
FT BINDING 29
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT BINDING 30
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT BINDING 69
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /note="via 3-oxoalanine"
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT BINDING 123
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:11124905"
FT BINDING 150
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:11124905"
FT BINDING 229
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:11124905"
FT BINDING 281
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT BINDING 282
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT BINDING 302
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:11124905"
FT MOD_RES 69
FT /note="3-oxoalanine (Cys)"
FT /evidence="ECO:0000269|PubMed:7628016,
FT ECO:0000269|PubMed:9342345"
FT CARBOHYD 158
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0000269|PubMed:19159218, ECO:0007744|PDB:1N2K"
FT CARBOHYD 184
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT CARBOHYD 350
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT DISULFID 156..172
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT DISULFID 161..168
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT DISULFID 300..414
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT DISULFID 488..500
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT DISULFID 489..502
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT DISULFID 493..499
FT /evidence="ECO:0000269|PubMed:12888274,
FT ECO:0007744|PDB:1N2K"
FT VAR_SEQ 1..84
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046190"
FT VARIANT 18
FT /note="A -> D (in MLD; enzyme activity reduced to 5% of
FT wild-type enzyme; dbSNP:rs199476339)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_054164"
FT VARIANT 29
FT /note="D -> N (in MLD; infantile-onset; causes a severe
FT reduction of enzyme activity; dbSNP:rs199476346)"
FT /evidence="ECO:0000269|PubMed:15326627"
FT /id="VAR_054165"
FT VARIANT 30
FT /note="D -> H (in MLD; enzyme activity reduced to 2.4% of
FT wild-type enzyme; dbSNP:rs199476340)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_054166"
FT VARIANT 32
FT /note="G -> S (in MLD; late-infantile form;
FT dbSNP:rs199476350)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054167"
FT VARIANT 52
FT /note="L -> P (in MLD; loss of enzymatic activity;
FT dbSNP:rs199476357)"
FT /evidence="ECO:0000269|PubMed:19606494"
FT /id="VAR_067414"
FT VARIANT 68
FT /note="L -> P (in MLD; late-infantile form;
FT dbSNP:rs199476351)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054168"
FT VARIANT 76
FT /note="L -> P (in dbSNP:rs199476362)"
FT /evidence="ECO:0000269|PubMed:9888390"
FT /id="VAR_007243"
FT VARIANT 82
FT /note="P -> L (in MLD; late-infantile-onset;
FT dbSNP:rs6151411)"
FT /evidence="ECO:0000269|PubMed:7581401, ECO:0000269|Ref.6"
FT /id="VAR_007244"
FT VARIANT 84
FT /note="R -> Q (in MLD; mild; dbSNP:rs74315458)"
FT /evidence="ECO:0000269|PubMed:1353340,
FT ECO:0000269|PubMed:18693274"
FT /id="VAR_007245"
FT VARIANT 84
FT /note="R -> W (in MLD; juvenile form; dbSNP:rs199476352)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054169"
FT VARIANT 86
FT /note="G -> D (in MLD; severe; no enzyme residual activity;
FT leads to a decreased stability of the mutant enzyme; causes
FT an arrest of the mutant enzyme polypeptide in a
FT prelysosomal compartment; dbSNP:rs74315460)"
FT /evidence="ECO:0000269|PubMed:10751093,
FT ECO:0000269|PubMed:7825603"
FT /id="VAR_007246"
FT VARIANT 94
FT /note="P -> A (in MLD; adult form; dbSNP:rs199476353)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054170"
FT VARIANT 95
FT /note="S -> N (in MLD; dbSNP:rs199476363)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007247"
FT VARIANT 96
FT /note="S -> F (in MLD; severe; dbSNP:rs74315456)"
FT /evidence="ECO:0000269|PubMed:1678251"
FT /id="VAR_007248"
FT VARIANT 96
FT /note="S -> L (in MLD; severe; no enzyme residual activity;
FT dbSNP:rs199476371)"
FT /evidence="ECO:0000269|PubMed:7825603"
FT /id="VAR_007249"
FT VARIANT 99
FT /note="G -> D (in MLD; adult type; dbSNP:rs74315455)"
FT /evidence="ECO:0000269|PubMed:1673291,
FT ECO:0000269|PubMed:21265945"
FT /id="VAR_007250"
FT VARIANT 99
FT /note="G -> V (in MLD; late-infantile form;
FT dbSNP:rs74315455)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054171"
FT VARIANT 119
FT /note="G -> R (in MLD; juvenile-onset; dbSNP:rs199476364)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007251"
FT VARIANT 122
FT /note="G -> S (in MLD; adult type; dbSNP:rs74315461)"
FT /evidence="ECO:0000269|PubMed:7902317"
FT /id="VAR_007252"
FT VARIANT 135
FT /note="L -> P (in MLD; dbSNP:rs121434215)"
FT /evidence="ECO:0000269|PubMed:9600244"
FT /id="VAR_007253"
FT VARIANT 136
FT /note="P -> L (in MLD; severe late-infantile type; loss of
FT enzymatic activity; dbSNP:rs74315462)"
FT /evidence="ECO:0000269|PubMed:7860068"
FT /id="VAR_007254"
FT VARIANT 136
FT /note="P -> S (in MLD; late-infantile form;
FT dbSNP:rs60504011)"
FT /evidence="ECO:0000269|PubMed:10477432,
FT ECO:0000269|PubMed:14680985"
FT /id="VAR_054172"
FT VARIANT 137
FT /note="Missing (in MLD)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_054173"
FT VARIANT 138
FT /note="H -> D (in MLD; significantly lower activity than
FT wild-type protein; dbSNP:rs199476358)"
FT /evidence="ECO:0000269|PubMed:19606494"
FT /id="VAR_067415"
FT VARIANT 143
FT /note="R -> G (in MLD; juvenile/adult-onset; generates 5%
FT as much activity as the parallel normal control;
FT dbSNP:rs199476373)"
FT /evidence="ECO:0000269|PubMed:11020646"
FT /id="VAR_054174"
FT VARIANT 148
FT /note="P -> L (in MLD; juvenile-onset; dbSNP:rs199476375)"
FT /evidence="ECO:0000269|PubMed:10381328"
FT /id="VAR_054175"
FT VARIANT 152
FT /note="D -> Y (in MLD; dbSNP:rs199476365)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007255"
FT VARIANT 153
FT /note="Q -> H (in MLD; late-infantile form; no enzyme
FT residual activity; dbSNP:rs199476377)"
FT /evidence="ECO:0000269|PubMed:8891236"
FT /id="VAR_054176"
FT VARIANT 154
FT /note="G -> D (in MLD; dbSNP:rs74315463)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_007256"
FT VARIANT 155
FT /note="P -> L (in MLD; juvenile-onset; dbSNP:rs74315464)"
FT /evidence="ECO:0000269|PubMed:14517960"
FT /id="VAR_054177"
FT VARIANT 155
FT /note="P -> R (in MLD; dbSNP:rs74315464)"
FT /id="VAR_007257"
FT VARIANT 156
FT /note="C -> R (in MLD; adult type; enzyme activity reduced
FT to 50% of wild-type enzyme; dbSNP:rs199476348)"
FT /evidence="ECO:0000269|PubMed:15326627"
FT /id="VAR_054178"
FT VARIANT 167
FT /note="P -> R (in MLD; dbSNP:rs74315465)"
FT /id="VAR_007258"
FT VARIANT 169
FT /note="D -> N (in MLD; dbSNP:rs74315466)"
FT /id="VAR_007259"
FT VARIANT 172
FT /note="C -> Y (in MLD; juvenile-onset; dbSNP:rs199476381)"
FT /evidence="ECO:0000269|PubMed:7581401"
FT /id="VAR_007260"
FT VARIANT 179
FT /note="I -> S (in MLD; mild; dbSNP:rs74315457)"
FT /evidence="ECO:0000269|PubMed:10533072,
FT ECO:0000269|PubMed:15326627, ECO:0000269|PubMed:18693274,
FT ECO:0000269|PubMed:20339381, ECO:0000269|PubMed:9600244"
FT /id="VAR_007261"
FT VARIANT 181
FT /note="L -> Q (in MLD; infantile form; dbSNP:rs199476378)"
FT /evidence="ECO:0000269|PubMed:14517960"
FT /id="VAR_054179"
FT VARIANT 190
FT /note="Q -> H (in MLD; no enzyme residual activity;
FT dbSNP:rs199476372)"
FT /evidence="ECO:0000269|PubMed:7825603"
FT /id="VAR_054180"
FT VARIANT 191
FT /note="P -> T (in MLD; juvenile-onset; dbSNP:rs199476374)"
FT /evidence="ECO:0000269|PubMed:10381328"
FT /id="VAR_054181"
FT VARIANT 193
FT /note="W -> C (in dbSNP:rs6151415)"
FT /evidence="ECO:0000269|PubMed:10477432,
FT ECO:0000269|PubMed:11456299, ECO:0000269|PubMed:15326627,
FT ECO:0000269|PubMed:1670590, ECO:0000269|PubMed:9888390,
FT ECO:0000269|Ref.6"
FT /id="VAR_007262"
FT VARIANT 201
FT /note="Y -> C (in MLD; juvenile-onset; results in highly
FT reduced enzyme activity and stability; the mutant enzyme is
FT kept in a prelysosomal compartment; dbSNP:rs199476345)"
FT /evidence="ECO:0000269|PubMed:10751093,
FT ECO:0000269|PubMed:18693274, ECO:0000269|PubMed:7581401"
FT /id="VAR_007263"
FT VARIANT 212
FT /note="A -> P (in MLD; loss of enzymatic activity;
FT dbSNP:rs199476341)"
FT /evidence="ECO:0000269|PubMed:18693274,
FT ECO:0000269|PubMed:19606494"
FT /id="VAR_054182"
FT VARIANT 212
FT /note="A -> V (in MLD; dbSNP:rs74315467)"
FT /evidence="ECO:0000269|PubMed:10477432,
FT ECO:0000269|PubMed:14517960, ECO:0000269|PubMed:7906588"
FT /id="VAR_007264"
FT VARIANT 217
FT /note="R -> H (in MLD; enzyme activity reduced to 15.6% of
FT wild-type enzyme; dbSNP:rs148403406)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_054183"
FT VARIANT 219
FT /note="F -> V (in MLD; enzyme activity reduced to less than
FT 1% of normal activity; dbSNP:rs199476383)"
FT /evidence="ECO:0000269|PubMed:15710861"
FT /id="VAR_054184"
FT VARIANT 224
FT /note="A -> V (in MLD; dbSNP:rs74315468)"
FT /evidence="ECO:0000269|PubMed:7906588"
FT /id="VAR_007265"
FT VARIANT 227
FT /note="H -> Y (in MLD; late-infantile form;
FT dbSNP:rs199476354)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054185"
FT VARIANT 231
FT /note="P -> T (in MLD; dbSNP:rs74315469)"
FT /id="VAR_007266"
FT VARIANT 244
FT /note="R -> C (in MLD; juvenile-onset; dbSNP:rs74315470)"
FT /id="VAR_007267"
FT VARIANT 244
FT /note="R -> H (in MLD; infantile-onset; dbSNP:rs199476366)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007268"
FT VARIANT 245
FT /note="G -> R (in MLD; severe; dbSNP:rs74315471)"
FT /evidence="ECO:0000269|PubMed:8101083"
FT /id="VAR_007269"
FT VARIANT 247
FT /note="F -> S (in MLD; dbSNP:rs199476384)"
FT /evidence="ECO:0000269|PubMed:14680985,
FT ECO:0000269|PubMed:20339381"
FT /id="VAR_054186"
FT VARIANT 250
FT /note="S -> Y (in MLD; infantile-onset; dbSNP:rs199476367)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007270"
FT VARIANT 253
FT /note="E -> K (in MLD; late-infantile; decreased enzymatic
FT activity; dbSNP:rs74315483)"
FT /evidence="ECO:0000269|PubMed:11941485,
FT ECO:0000269|PubMed:18693274"
FT /id="VAR_054187"
FT VARIANT 255
FT /note="D -> H (in MLD; late-infantile form; no enzyme
FT residual activity; leads to a decreased stability of the
FT mutant enzyme; causes an arrest of the mutant enzyme
FT polypeptide in a prelysosomal compartment;
FT dbSNP:rs80338819)"
FT /evidence="ECO:0000269|PubMed:10477432,
FT ECO:0000269|PubMed:10751093"
FT /id="VAR_054188"
FT VARIANT 274
FT /note="T -> M (in MLD; severe; 35% of normal activity;
FT dbSNP:rs74315472)"
FT /evidence="ECO:0000269|PubMed:7825603,
FT ECO:0000269|PubMed:8104633, ECO:0000269|PubMed:8723680"
FT /id="VAR_007271"
FT VARIANT 281
FT /note="D -> Y (in MLD; dbSNP:rs199476386)"
FT /evidence="ECO:0000269|PubMed:10533072"
FT /id="VAR_054189"
FT VARIANT 282
FT /note="N -> S (in MLD; enzyme activity reduced to 0.6% of
FT wild-type enzyme; dbSNP:rs199476342)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_054190"
FT VARIANT 286
FT /note="T -> P (in MLD; adult type; dbSNP:rs28940894)"
FT /evidence="ECO:0000269|PubMed:11061266"
FT /id="VAR_054191"
FT VARIANT 288
FT /note="R -> C (in MLD; dbSNP:rs74315473)"
FT /evidence="ECO:0000269|PubMed:20339381"
FT /id="VAR_007272"
FT VARIANT 288
FT /note="R -> H (in MLD; adult form; dbSNP:rs199476355)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054192"
FT VARIANT 293
FT /note="G -> D (in MLD; late-onset; dbSNP:rs199476387)"
FT /evidence="ECO:0000269|PubMed:15026521"
FT /id="VAR_054193"
FT VARIANT 293
FT /note="G -> S (in MLD; adult type; causes a severe
FT reduction of enzyme activity; dbSNP:rs199476349)"
FT /evidence="ECO:0000269|PubMed:15326627"
FT /id="VAR_054194"
FT VARIANT 294
FT /note="C -> Y (in MLD; juvenile-onset; causes a severe
FT reduction of enzyme activity; dbSNP:rs199476347)"
FT /evidence="ECO:0000269|PubMed:15326627"
FT /id="VAR_054195"
FT VARIANT 295
FT /note="S -> Y (in MLD; severe; dbSNP:rs74315474)"
FT /evidence="ECO:0000269|PubMed:7906588"
FT /id="VAR_007273"
FT VARIANT 298
FT /note="L -> S (in MLD; late-infantile form; complete loss
FT of enzyme activity; dbSNP:rs199476389)"
FT /evidence="ECO:0000269|PubMed:9819708"
FT /id="VAR_054196"
FT VARIANT 300
FT /note="C -> F (in MLD; late-infantile-onset; enzyme
FT activity reduced to less than 1%; the mutant protein is
FT more rapidly degraded in lysosomes; strongly interferes
FT with the octamerization process of the enzyme at low pH;
FT dbSNP:rs74315484)"
FT /evidence="ECO:0000269|PubMed:10220151,
FT ECO:0000269|PubMed:12503099, ECO:0000269|PubMed:12788103"
FT /id="VAR_008132"
FT VARIANT 302
FT /note="K -> N (in MLD; enzyme activity reduced to 2.8% of
FT wild-type enzyme; dbSNP:rs199476343)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_054197"
FT VARIANT 304
FT /note="T -> M (in MLD; loss of enzymatic activity;
FT dbSNP:rs199476359)"
FT /evidence="ECO:0000269|PubMed:19606494"
FT /id="VAR_067416"
FT VARIANT 306
FT /note="Y -> H (in MLD; juvenile-onset; dbSNP:rs199476379)"
FT /evidence="ECO:0000269|PubMed:14517960"
FT /id="VAR_054198"
FT VARIANT 307
FT /note="E -> K (in MLD; loss of enzymatic activity;
FT dbSNP:rs199476360)"
FT /evidence="ECO:0000269|PubMed:19606494"
FT /id="VAR_067417"
FT VARIANT 308
FT /note="G -> D (in MLD; late-infantile form;
FT dbSNP:rs199476356)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054199"
FT VARIANT 308
FT /note="G -> V (in MLD; late-infantile form; no enzyme
FT residual activity; dbSNP:rs199476356)"
FT /evidence="ECO:0000269|PubMed:8891236"
FT /id="VAR_054200"
FT VARIANT 309
FT /note="G -> S (in MLD; severe; 13% of normal activity;
FT dbSNP:rs74315459)"
FT /evidence="ECO:0000269|PubMed:15326627,
FT ECO:0000269|PubMed:8101038"
FT /id="VAR_007274"
FT VARIANT 311
FT /note="R -> Q (in MLD; juvenile-onset; dbSNP:rs199476382)"
FT /evidence="ECO:0000269|PubMed:7581401"
FT /id="VAR_007275"
FT VARIANT 312
FT /note="E -> D (in MLD; low amounts of residual enzyme
FT activity; leads to a decreased stability of the mutant
FT enzyme; dbSNP:rs199476390)"
FT /evidence="ECO:0000269|PubMed:10751093"
FT /id="VAR_054201"
FT VARIANT 314
FT /note="A -> T (in MLD; infantile-onset; dbSNP:rs199476368)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007276"
FT VARIANT 325
FT /note="G -> S (in MLD; juvenile-onset; dbSNP:rs148092995)"
FT /evidence="ECO:0000269|PubMed:14517960"
FT /id="VAR_054202"
FT VARIANT 327
FT /note="T -> I (in MLD; late-infantile form)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_054203"
FT VARIANT 335
FT /note="D -> V (in MLD; late-infantile-onset; loss of
FT enzymatic activity; dbSNP:rs74315475)"
FT /evidence="ECO:0000269|PubMed:10381328,
FT ECO:0000269|PubMed:14517960, ECO:0000269|PubMed:20339381,
FT ECO:0000269|PubMed:7581401, ECO:0000269|PubMed:8723680"
FT /id="VAR_007277"
FT VARIANT 350
FT /note="N -> S (often found in association with a nucleotide
FT substitution in the polyadenylation signal downstream of
FT the stop codon; this association defines an ARSA
FT pseudodeficiency allele found in individuals with low
FT enzymatic activities but no clinical manifestations; no
FT effect on activity; no effect on protein abundance; loss of
FT N-glycosylation; dbSNP:rs2071421)"
FT /evidence="ECO:0000269|PubMed:10477432,
FT ECO:0000269|PubMed:11941485, ECO:0000269|PubMed:15026521,
FT ECO:0000269|PubMed:2574462, ECO:0000269|Ref.6"
FT /id="VAR_007278"
FT VARIANT 356
FT /note="F -> V (in dbSNP:rs6151422)"
FT /evidence="ECO:0000269|Ref.6"
FT /id="VAR_018838"
FT VARIANT 367
FT /note="K -> N (in MLD; dbSNP:rs199476369)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007279"
FT VARIANT 370
FT /note="R -> Q (in MLD; mild; dbSNP:rs74315477)"
FT /id="VAR_007280"
FT VARIANT 370
FT /note="R -> W (in MLD; severe; no enzyme residual activity;
FT dbSNP:rs74315476)"
FT /evidence="ECO:0000269|PubMed:18693274,
FT ECO:0000269|PubMed:7825603"
FT /id="VAR_007281"
FT VARIANT 376
FT /note="Y -> N (in MLD; enzyme activity reduced to 4.7% of
FT wild-type enzyme; dbSNP:rs199476344)"
FT /evidence="ECO:0000269|PubMed:18693274"
FT /id="VAR_054204"
FT VARIANT 377
FT /note="P -> L (in MLD; severe; dbSNP:rs74315478)"
FT /evidence="ECO:0000269|PubMed:10477432"
FT /id="VAR_007282"
FT VARIANT 381
FT /note="D -> E (in MLD; early-infantile form;
FT dbSNP:rs6151425)"
FT /id="VAR_054205"
FT VARIANT 382
FT /note="E -> K (in MLD; intermediate; dbSNP:rs74315479)"
FT /evidence="ECO:0000269|PubMed:20339381"
FT /id="VAR_007283"
FT VARIANT 384
FT /note="R -> C (in MLD; dbSNP:rs199476370)"
FT /evidence="ECO:0000269|PubMed:9090526"
FT /id="VAR_007284"
FT VARIANT 390
FT /note="R -> Q (in MLD; juvenile-onset; dbSNP:rs199476391)"
FT /evidence="ECO:0000269|PubMed:20339381,
FT ECO:0000269|PubMed:9452102"
FT /id="VAR_007285"
FT VARIANT 390
FT /note="R -> W (in MLD; late-infantile and juvenile-onset;
FT dbSNP:rs74315480)"
FT /evidence="ECO:0000269|PubMed:18693274,
FT ECO:0000269|PubMed:20339381, ECO:0000269|PubMed:7581401"
FT /id="VAR_007286"
FT VARIANT 391
FT /note="T -> S (retains 90% of activity; dbSNP:rs743616)"
FT /evidence="ECO:0000269|PubMed:10477432,
FT ECO:0000269|PubMed:11061266, ECO:0000269|PubMed:11456299,
FT ECO:0000269|PubMed:11941485, ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15326627, ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:1670590, ECO:0000269|PubMed:9888390,
FT ECO:0000269|Ref.6"
FT /id="VAR_007287"
FT VARIANT 397
FT /note="H -> Y (in MLD; adult-onset; dbSNP:rs199476376)"
FT /evidence="ECO:0000269|PubMed:10381328,
FT ECO:0000269|PubMed:20339381, ECO:0000269|PubMed:9452102"
FT /id="VAR_007288"
FT VARIANT 398
FT /note="Missing (in MLD)"
FT /id="VAR_007289"
FT VARIANT 406..408
FT /note="Missing (in MLD; late-infantile-onset)"
FT /evidence="ECO:0000269|PubMed:9490297"
FT /id="VAR_007290"
FT VARIANT 406
FT /note="S -> G (in MLD; loss of enzymatic activity;
FT dbSNP:rs199476361)"
FT /evidence="ECO:0000269|PubMed:19606494"
FT /id="VAR_067418"
FT VARIANT 408
FT /note="T -> I (in MLD; adult type; dbSNP:rs28940895)"
FT /evidence="ECO:0000269|PubMed:11456299"
FT /id="VAR_054206"
FT VARIANT 409
FT /note="T -> I (in MLD; mild; dbSNP:rs74315481)"
FT /evidence="ECO:0000269|PubMed:21265945,
FT ECO:0000269|PubMed:7909527"
FT /id="VAR_054207"
FT VARIANT 425
FT /note="P -> T (in MLD; juvenile-onset; retains about 12% of
FT specific enzyme activity; the mutant protein is unstable;
FT results in more rapid enzyme degradation in lysosomes;
FT addition of the cysteine protease inhibitor leupeptin
FT increases the amount of the enzyme activity; displays a
FT modest reduction in the octamerization process of the
FT enzyme at low pH; dbSNP:rs74315485)"
FT /evidence="ECO:0000269|PubMed:10220151,
FT ECO:0000269|PubMed:12503099, ECO:0000269|PubMed:12788103"
FT /id="VAR_008133"
FT VARIANT 426
FT /note="P -> L (in MLD; juvenile/adult-onset; mild; common
FT mutation; decreased enzyme activity; dbSNP:rs28940893)"
FT /evidence="ECO:0000269|PubMed:10381328,
FT ECO:0000269|PubMed:11941485, ECO:0000269|PubMed:14517960,
FT ECO:0000269|PubMed:14680985, ECO:0000269|PubMed:15326627,
FT ECO:0000269|PubMed:1670590, ECO:0000269|PubMed:20339381,
FT ECO:0000269|PubMed:8095918"
FT /id="VAR_007291"
FT VARIANT 428
FT /note="L -> P (in MLD; late-infantile form;
FT dbSNP:rs199476392)"
FT /evidence="ECO:0000269|PubMed:18693274,
FT ECO:0000269|PubMed:9272717"
FT /id="VAR_054208"
FT VARIANT 429
FT /note="Y -> S (in MLD; adult-onset; dbSNP:rs199476380)"
FT /evidence="ECO:0000269|PubMed:14517960"
FT /id="VAR_054209"
FT VARIANT 440
FT /note="N -> S (in dbSNP:rs6151427)"
FT /evidence="ECO:0000269|Ref.6"
FT /id="VAR_018839"
FT VARIANT 464
FT /note="A -> V"
FT /evidence="ECO:0000269|PubMed:9888390"
FT /id="VAR_007292"
FT VARIANT 469
FT /note="A -> G (in MLD; early-infantile form;
FT dbSNP:rs199476385)"
FT /evidence="ECO:0000269|PubMed:14680985"
FT /id="VAR_054210"
FT VARIANT 489
FT /note="C -> G (in MLD; late-onset; dbSNP:rs199476388)"
FT /evidence="ECO:0000269|PubMed:15026521"
FT /id="VAR_054211"
FT VARIANT 496
FT /note="R -> H (in dbSNP:rs6151428)"
FT /evidence="ECO:0000269|PubMed:9090526,
FT ECO:0000269|PubMed:9744473, ECO:0000269|Ref.6"
FT /id="VAR_007293"
FT MUTAGEN 69..70
FT /note="CT->TC: Strongly reduces formation of 3-oxoalanine
FT (also known as C-formylglycine, FGly)."
FT /evidence="ECO:0000269|PubMed:9342345"
FT MUTAGEN 69
FT /note="C->A: Abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:11124905"
FT MUTAGEN 69
FT /note="C->S: Abolishes formation of 3-oxoalanine (also
FT known as C-formylglycine, FGly). Strongly decreases enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:11124905,
FT ECO:0000269|PubMed:9342345"
FT CONFLICT 290
FT /note="S -> P (in Ref. 5; AK098659)"
FT /evidence="ECO:0000305"
FT STRAND 22..30
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 37..39
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 47..54
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 56..63
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 65..68
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 69..78
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 82..85
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 107..112
FT /evidence="ECO:0007829|PDB:1AUK"
FT TURN 113..115
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 117..122
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 130..132
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 136..139
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 142..146
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 153..155
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 159..162
FT /evidence="ECO:0007829|PDB:1AUK"
FT TURN 163..165
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 181..183
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 186..191
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 194..196
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 197..214
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 219..224
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 229..231
FT /evidence="ECO:0007829|PDB:1AUK"
FT TURN 236..241
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 242..244
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 245..267
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 271..273
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 274..282
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 286..291
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 304..306
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 307..310
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 315..317
FT /evidence="ECO:0007829|PDB:1AUK"
FT TURN 319..321
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 324..327
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 333..335
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 336..343
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 359..363
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 372..375
FT /evidence="ECO:0007829|PDB:1AUK"
FT TURN 382..384
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 387..391
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 394..400
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 404..406
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 408..410
FT /evidence="ECO:0007829|PDB:1E1Z"
FT HELIX 412..414
FT /evidence="ECO:0007829|PDB:1AUK"
FT STRAND 421..430
FT /evidence="ECO:0007829|PDB:1AUK"
FT TURN 431..433
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 450..469
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 477..479
FT /evidence="ECO:0007829|PDB:1AUK"
FT HELIX 483..485
FT /evidence="ECO:0007829|PDB:1AUK"
FT TURN 496..499
FT /evidence="ECO:0007829|PDB:1AUK"
SQ SEQUENCE 507 AA; 53588 MW; 3DDBE1378B4176A6 CRC64;
MGAPRSLLLA LAAGLAVARP PNIVLIFADD LGYGDLGCYG HPSSTTPNLD QLAAGGLRFT
DFYVPVSLCT PSRAALLTGR LPVRMGMYPG VLVPSSRGGL PLEEVTVAEV LAARGYLTGM
AGKWHLGVGP EGAFLPPHQG FHRFLGIPYS HDQGPCQNLT CFPPATPCDG GCDQGLVPIP
LLANLSVEAQ PPWLPGLEAR YMAFAHDLMA DAQRQDRPFF LYYASHHTHY PQFSGQSFAE
RSGRGPFGDS LMELDAAVGT LMTAIGDLGL LEETLVIFTA DNGPETMRMS RGGCSGLLRC
GKGTTYEGGV REPALAFWPG HIAPGVTHEL ASSLDLLPTL AALAGAPLPN VTLDGFDLSP
LLLGTGKSPR QSLFFYPSYP DEVRGVFAVR TGKYKAHFFT QGSAHSDTTA DPACHASSSL
TAHEPPLLYD LSKDPGENYN LLGGVAGATP EVLQALKQLQ LLKAQLDAAV TFGPSQVARG
EDPALQICCH PGCTPRPACC HCPDPHA
