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 27-MAR-2024, entry version 240. 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; 91. DR IntAct; P15289; 32. DR MINT; P15289; -. DR STRING; 9606.ENSP00000216124; -. DR BindingDB; P15289; -. 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 GlyCosmos; P15289; 3 sites, 27 glycans. DR GlyGen; P15289; 4 sites, 27 N-linked glycans (4 sites), 1 O-linked glycan (1 site). DR iPTMnet; P15289; -. DR PhosphoSitePlus; P15289; -. DR SwissPalm; P15289; -. DR BioMuta; ARSA; -. DR EPD; P15289; -. DR jPOST; P15289; -. DR MassIVE; P15289; -. DR MaxQB; P15289; -. DR PaxDb; 9606-ENSP00000216124; -. DR PeptideAtlas; P15289; -. DR ProteomicsDB; 31108; -. DR ProteomicsDB; 53123; -. [P15289-1] DR Pumba; P15289; -. DR Antibodypedia; 215; 523 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 AGR; HGNC:713; -. 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; 2913702at2759; -. DR PhylomeDB; P15289; -. DR BioCyc; MetaCyc:HS02032-MONOMER; -. DR PathwayCommons; P15289; -. DR Reactome; R-HSA-1663150; The activation of arylsulfatases. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9840310; Glycosphingolipid catabolism. DR SABIO-RK; P15289; -. DR SignaLink; P15289; -. DR SIGNOR; P15289; -. DR BioGRID-ORCS; 410; 36 hits in 1164 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 103 other cell types or tissues. DR ExpressionAtlas; P15289; baseline and differential. 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 CDD; cd16158; ARSA; 1. DR Gene3D; 3.30.1120.10; -; 1. DR Gene3D; 3.40.720.10; Alkaline Phosphatase, subunit A; 1. DR InterPro; IPR017850; Alkaline_phosphatase_core_sf. DR InterPro; IPR024607; Sulfatase_CS. DR InterPro; IPR000917; Sulfatase_N. DR PANTHER; PTHR42693:SF11; ARYLSULFATASE A; 1. DR PANTHER; PTHR42693; ARYLSULFATASE FAMILY MEMBER; 1. DR Pfam; PF00884; Sulfatase; 1. DR Pfam; PF14707; Sulfatase_C; 1. DR SUPFAM; SSF53649; Alkaline phosphatase-like; 1. DR PROSITE; PS00523; SULFATASE_1; 1. DR PROSITE; PS00149; SULFATASE_2; 1. DR Genevisible; P15289; HS. 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; uncertain significance; FT early-infantile form; dbSNP:rs6151425)" FT /evidence="ECO:0000269|PubMed:14680985" 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 //