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 01-MAY-2013, entry version 153. DE RecName: Full=Arylsulfatase A; DE Short=ASA; DE EC=3.1.6.8; 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=2562955; RA Stein C., Gieselmann V., Kreysing J., Schmidt B., Pohlmann R., RA Waheed A., 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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; RP SER-350; 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., RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J., RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G., RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R., RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E., RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G., RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A., RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C., RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A., RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M., RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T., RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J., RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T., RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T., RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L., RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M., RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L., RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L., RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N., RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T., RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I., RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H., RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L., RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z., RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P., RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S., RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J., RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T., RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J., RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R., RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P., RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E., RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X., RA Khan A.S., Lane L., Tilahun Y., Wright H.; RT "The DNA sequence of human chromosome 22."; RL Nature 402:489-495(1999). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT RP 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 RT project: 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, MASS SPECTROMETRY, OXOALANINE AT CYS-69, AND RP ABSENCE 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 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., RA Uziel G., Mancini G.M., Zammarchi E., Donati M.A., Kleijer W.J., RA Filocamo M., Carrozzo R., Carella M., Ballabio A.; RT "Molecular and functional analysis of SUMF1 mutations in multiple RT sulfatase deficiency."; RL Hum. Mutat. 23:576-581(2004). RN [12] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-158 AND ASN-350, AND MASS RP SPECTROMETRY. 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 RT multiple enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [13] 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., RA von Figura K., Saenger W.; RT "Crystal structure of human arylsulfatase A: the aldehyde function and RT the metal ion at the active site suggest a novel mechanism for sulfate RT ester hydrolysis."; RL Biochemistry 37:3654-3664(1998). RN [14] 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 RT into the interaction between human arylsulfatase A and its substrates RT during catalysis."; RL J. Mol. Biol. 305:269-277(2001). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 19-507, SUBUNIT, RP GLYCOSYLATION AT ASN-158 AND ASN-184, ACTIVE SITE, ENZYME REGULATION, RP CALCIUM-BINDING, AND 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 [16] 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 RT formylglycine-generating enzyme."; RL Proc. Natl. Acad. Sci. U.S.A. 103:81-86(2006). RN [17] 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 [18] RP VARIANT SER-350, AND ASSOCIATION WITH ARYLSULFATASE A RP PSEUDODEFICIENCY. 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 RT and N-glycosylation site."; RL Proc. Natl. Acad. Sci. U.S.A. 86:9436-9440(1989). RN [19] RP VARIANT MLD ASP-99. RX PubMed=1673291; RA Kondo R., Wakamatsu N., Yoshino H., Fukuhara N., Miyatake T., RA Tsuji S.; RT "Identification of a mutation in the arylsulfatase A gene of a patient RT with adult-type metachromatic leukodystrophy."; RL Am. J. Hum. Genet. 48:971-978(1991). RN [20] 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 [21] RP VARIANT MLD LEU-426, AND VARIANTS CYS-193 AND SER-391. RX PubMed=1670590; 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 [22] 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 [23] 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 [24] 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 [25] 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 [26] 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., RA Kondo R., 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 [27] 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 [28] 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- RT infantile metachromatic leukodystrophy."; RL Hum. Mutat. 2:261-267(1993). RN [29] 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 [30] 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 RT metachromatic leukodystrophy in a small geographic area."; RL Am. J. Hum. Genet. 56:51-57(1995). RN [31] 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 RT instability and loss of activity of the mutant enzyme."; RL Hum. Genet. 95:201-204(1995). RN [32] 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 [33] 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 RT form of metachromatic leukodystrophy."; RL Brain Dev. 18:400-403(1996). RN [34] 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>3.3.CO;2-1; RA Hess B., Kafert S., Heinisch U., Wenger D.A., Zlotogora J., RA Gieselmann V.; RT "Characterization of two arylsulfatase A missense mutations D335V and RT T274M causing late infantile metachromatic leukodystrophy."; RL Hum. Mutat. 7:311-317(1996). RN [35] RP VARIANT MLD PRO-428. RX PubMed=9272717; RA Regis S., Filocamo M., Stroppiano M., Corsolini F., Gatti R.; RT "A T > C transition causing a Leu > Pro substitution in a conserved RT region of the arylsulfatase A gene in a late infantile metachromatic RT leukodystrophy patient."; RL Clin. Genet. 52:65-67(1997). RN [36] RP VARIANTS MLD ASN-95; ARG-119; TYR-152; HIS-244; TYR-250; THR-314; RP ASN-367 AND CYS-384, AND VARIANT HIS-496. RX PubMed=9090526; RX DOI=10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.3.CO;2-S; RA Draghia R., Letourneur F., Drugan C., Manicom J., Blanchot C., RA Kahn A., Poenaru L., Caillaud C.; RT "Metachromatic leukodystrophy: identification of the first deletion in RT exon 1 and of nine novel point mutations in the arylsulfatase A RT gene."; RL Hum. Mutat. 9:234-242(1997). RN [37] 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., RA Gatti R.; RT "A 9-bp deletion (2320del9) on the background of the arylsulfatase A RT pseudodeficiency allele in a metachromatic leukodystrophy patient and RT in a patient with nonprogressive neurological symptoms."; RL Hum. Genet. 102:50-53(1998). RN [38] 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 RT leukodystrophy patients who carry the T799G mutation and show RT different phenotypes; description of a novel null-type mutation."; RL Hum. Genet. 102:459-463(1998). RN [39] RP ERRATUM. 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 [40] RP VARIANT HIS-496. RX PubMed=9744473; RX DOI=10.1002/(SICI)1098-1004(1998)12:4<238::AID-HUMU3>3.3.CO;2-N; 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 [41] RP VARIANTS MLD GLN-390 AND TYR-397. RX PubMed=9452102; RA Coulter-Mackie M.B., Gagnier L.; RT "Two novel mutations in the arylsulfatase A gene associated with RT juvenile (R390Q) and adult onset (H397Y) metachromatic RT leukodystrophy."; RL Hum. Mutat. Suppl. 1:S254-S256(1998). RN [42] 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 [43] 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 RT 459+1G>A within a family with metachromatic leukodystrophy: molecular RT basis of phenotypic heterogeneity."; RL Hum. Mutat. 13:61-68(1999). RN [44] 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 RT molecular lesions: C300F, P425T, g.1190-1191insC, and g.2408delC."; RL Hum. Mutat. 13:337-338(1999). RN [45] 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>3.3.CO;2-C; 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 RT studies in Spanish metachromatic leukodystrophy patients."; RL Hum. Mutat. 14:240-248(1999). RN [46] 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 RT in an adult onset case."; RL Hum. Mutat. 14:447-447(1999). RN [47] 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 RT and identification of novel missense mutations (P148L and P191T) RT causing the juvenile-onset disease."; RL Mol. Genet. Metab. 67:206-212(1999). RN [48] RP VARIANTS MLD ASP-86; CYS-201; HIS-255 AND ASP-312, AND RP CHARACTERIZATION OF VARIANTS MLD ASP-86; CYS-201; HIS-255 AND ASP-312. 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., RA Zlotogora J., Baumann N., Gieselmann V.; RT "Characterization of four arylsulfatase A missense mutations G86D, RT Y201C, D255H, and E312D causing metachromatic leukodystrophy."; RL Am. J. Med. Genet. 91:68-73(2000). RN [49] RP VARIANT MLD PRO-286, AND VARIANT SER-391. RX PubMed=11061266; 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 [50] 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 RT family."; RL Pediatr. Neurol. 23:173-176(2000). RN [51] 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 RT isolated peripheral neuropathy: compound heterozygosity for the RT IVS2+1G-->A mutation and a newly identified missense mutation RT (Thr408Ile) in a Spanish family."; RL Ann. Neurol. 50:108-112(2001). RN [52] RP VARIANT MLD LYS-253, AND 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 RT to enzyme activity reduction and metachromatic leukodystrophy RT severity."; RL Hum. Genet. 110:351-355(2002). RN [53] 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 [54] 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 [55] RP VARIANTS MLD LEU-155; GLN-181; VAL-212; HIS-306; SER-325; VAL-335; RP LEU-426 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 [56] 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 RT with metachromatic leukodystrophy."; RL Mol. Genet. Metab. 80:360-363(2003). RN [57] 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 RP VARIANTS MLD 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: RT phenotype and expression studies in nine Czech and Slovak patients."; RL Am. J. Med. Genet. A 129:277-281(2004). RN [58] 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 [59] 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 RT gene."; RL Arch. Neurol. 62:309-313(2005). RN [60] 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; RP ASN-376; TRP-390 AND PRO-428, AND CHARACTERIZATION OF VARIANTS MLD RP ASP-18; HIS-30; PRO-212; HIS-217; SER-282; ASN-302; TRP-370 AND RP 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., RA Filocamo M.; RT "Molecular analysis of ARSA and PSAP genes in twenty-one Italian RT patients with metachromatic leukodystrophy: identification and RT functional characterization of 11 novel ARSA alleles."; RL Hum. Mutat. 29:E220-E230(2008). RN [61] RP VARIANTS MLD PRO-52; ASP-138; PRO-212; MET-304; LYS-307 AND GLY-406, RP AND CHARACTERIZATION OF VARIANTS MLD PRO-52; ASP-138; PRO-212; RP MET-304; LYS-307 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 [62] RP VARIANTS MLD SER-179; SER-247; CYS-288; VAL-335; LYS-382; GLN-390; RP TRP-390; 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 [63] 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 RT ARSA mutations: a case report and phenotypic comparison with a RT previously reported case."; RL Psychiatry Clin. Neurosci. 65:105-108(2011). CC -!- FUNCTION: Hydrolyzes cerebroside sulfate. CC -!- CATALYTIC ACTIVITY: A cerebroside 3-sulfate + H(2)O = a CC cerebroside + sulfate. CC -!- COFACTOR: Binds 1 calcium ion per subunit. CC -!- ENZYME REGULATION: Inhibited by phosphate. The phosphate forms a CC covalent bond with the active site 3-oxoalanine. CC -!- SUBUNIT: Homodimer at neutral pH and homooctamer at acidic pH. CC Exists both as a single chain of 58 kDa (component A) or as a CC chain of 50 kDa (component B) linked by disulfide bond(s) to a 7 CC kDa chain (component C). Interacts with SUMF1. CC -!- SUBCELLULAR LOCATION: Lysosome. 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 Note=No experimental confirmation available; CC -!- PTM: The conversion to 3-oxoalanine (also known as C- CC formylglycine, FGly), of a serine or cysteine residue in CC prokaryotes and of a cysteine residue in eukaryotes, is critical CC for catalytic activity. This post-translational modification is CC severely defective in multiple sulfatase deficiency (MSD). CC -!- DISEASE: Leukodystrophy metachromatic (MLD) [MIM:250100]: A CC leukodystrophy due to a lysosomal storage defect. Characterized by CC intralysosomal storage of cerebroside-3-sulfate in neural and non- CC neural tissues, with a diffuse loss of myelin in the central CC nervous system. Progressive demyelination causes a variety of CC neurological symptoms, including gait disturbances, ataxias, CC optical atrophy, dementia, seizures, and spastic tetraparesis. CC Three forms of the disease can be distinguished according to the CC age at onset: late-infantile, juvenile and adult. Note=The disease CC is caused by mutations affecting the gene represented in this CC entry. CC -!- DISEASE: Multiple sulfatase deficiency (MSD) [MIM:272200]: A CC clinically and biochemically heterogeneous disorder caused by the CC simultaneous impairment of all sulfatases, due to defective post- CC translational modification and activation. It combines features of CC individual sulfatase deficiencies such as metachromatic CC leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, CC hydrocephalus, ichthyosis, neurologic deterioration and CC developmental delay. Note=The protein represented in this entry is CC involved in disease pathogenesis. Arylsulfatase A activity is CC impaired in multiple sulfatase deficiency due to mutations in CC SUMF1. SUMF1 mutations result in defective post-translational CC modification of ARSA at residue Cys-69 that is not converted to 3- CC oxoalanine. CC -!- MISCELLANEOUS: The metal cofactor was first identified as CC magnesium ion, based on the structure of the recombinant protein, CC but when purified from human placenta, the protein contains 1 CC calcium ion per subunit. CC -!- SIMILARITY: Belongs to the sulfatase family. CC -!- SEQUENCE CAUTION: CC Sequence=AAB03341.1; Type=Erroneous initiation; CC Sequence=BAH11167.1; Type=Erroneous initiation; CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ARSA"; 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="http://en.wikipedia.org/wiki/Arylsulfatase_A"; CC -!- WEB RESOURCE: Name=Arylsulfatase A (ARSA); Note=Leiden Open CC Variation Database (LOVD); CC URL="http://grenada.lumc.nl/LOVD2/mendelian_genes/home.php?select_db=ARSA"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs 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 IPI; IPI00744184; -. DR IPI; IPI00853468; -. 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. DR UniGene; Hs.731715; -. DR UniGene; Hs.88251; -. 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 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 ProteinModelPortal; P15289; -. DR IntAct; P15289; 4. DR STRING; 9606.ENSP00000216124; -. DR GlycoSuiteDB; P15289; -. DR PaxDb; P15289; -. DR PRIDE; P15289; -. DR DNASU; 410; -. DR Ensembl; ENST00000216124; ENSP00000216124; ENSG00000100299. DR Ensembl; ENST00000356098; ENSP00000348406; ENSG00000100299. DR Ensembl; ENST00000395619; ENSP00000378981; ENSG00000100299. DR Ensembl; ENST00000395621; ENSP00000378983; ENSG00000100299. DR Ensembl; ENST00000453344; ENSP00000412542; ENSG00000100299. DR Ensembl; ENST00000547307; ENSP00000448440; ENSG00000100299. DR Ensembl; ENST00000547805; ENSP00000448932; ENSG00000100299. DR GeneID; 410; -. DR KEGG; hsa:410; -. DR UCSC; uc003bna.4; human. DR CTD; 410; -. DR GeneCards; GC22M051063; -. DR HGNC; HGNC:713; ARSA. DR HPA; CAB025183; -. DR HPA; HPA005554; -. DR MIM; 250100; phenotype. DR MIM; 272200; phenotype. DR MIM; 607574; gene. DR neXtProt; NX_P15289; -. DR Orphanet; 512; Metachromatic leukodystrophy. DR Orphanet; 751; Pseudoarylsulfatase A deficiency. DR PharmGKB; PA25005; -. DR eggNOG; COG3119; -. DR HOGENOM; HOG000135352; -. DR HOVERGEN; HBG004283; -. DR InParanoid; P15289; -. DR KO; K01134; -. DR OrthoDB; EOG4MKNG4; -. DR PhylomeDB; P15289; -. DR BRENDA; 3.1.6.8; 2681. DR Reactome; REACT_111217; Metabolism. DR Reactome; REACT_17015; Metabolism of proteins. DR ChEMBL; CHEMBL2193; -. DR DrugBank; DB01141; Micafungin. DR EvolutionaryTrace; P15289; -. DR GenomeRNAi; 410; -. DR NextBio; 1725; -. DR PMAP-CutDB; P15289; -. DR ArrayExpress; P15289; -. DR Bgee; P15289; -. DR CleanEx; HS_ARSA; -. DR Genevestigator; P15289; -. DR GermOnline; ENSG00000100299; Homo sapiens. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0004065; F:arylsulfatase activity; TAS:ProtInc. DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB. DR GO; GO:0004098; F:cerebroside-sulfatase activity; TAS:Reactome. DR GO; GO:0006687; P:glycosphingolipid metabolic process; TAS:Reactome. DR GO; GO:0006644; P:phospholipid metabolic process; TAS:Reactome. DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome. DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome. DR Gene3D; 3.40.720.10; -; 1. DR InterPro; IPR017849; Alkaline_Pase-like_a/b/a. DR InterPro; IPR017850; Alkaline_phosphatase_core. DR InterPro; IPR000917; Sulfatase. DR InterPro; IPR024607; Sulfatase_CS. DR Pfam; PF00884; Sulfatase; 1. DR SUPFAM; SSF53649; Alkaline_phosphatase_core; 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; Complete proteome; KW Direct protein sequencing; Disease mutation; Disulfide bond; KW Glycoprotein; Hydrolase; Ichthyosis; Leukodystrophy; Lysosome; KW Metachromatic leukodystrophy; Metal-binding; Polymorphism; KW Reference proteome; Signal. FT SIGNAL 1 18 FT CHAIN 19 507 Arylsulfatase A. FT /FTId=PRO_0000033417. FT CHAIN 19 444 Arylsulfatase A component B. FT /FTId=PRO_0000033418. FT CHAIN 448 507 Arylsulfatase A component C. FT /FTId=PRO_0000033419. FT ACT_SITE 125 125 FT METAL 29 29 Calcium. FT METAL 30 30 Calcium. FT METAL 69 69 Calcium; via 3-oxoalanine. FT METAL 281 281 Calcium. FT METAL 282 282 Calcium. FT BINDING 123 123 Substrate. FT BINDING 150 150 Substrate. FT BINDING 229 229 Substrate. FT BINDING 302 302 Substrate. FT MOD_RES 69 69 3-oxoalanine (Cys). FT CARBOHYD 158 158 N-linked (GlcNAc...). FT CARBOHYD 184 184 N-linked (GlcNAc...). FT CARBOHYD 350 350 N-linked (GlcNAc...). FT DISULFID 156 172 FT DISULFID 161 168 FT DISULFID 300 414 FT DISULFID 488 500 FT DISULFID 489 502 FT DISULFID 493 499 FT VAR_SEQ 1 84 Missing (in isoform 2). FT /FTId=VSP_046190. FT VARIANT 18 18 A -> D (in MLD; enzyme activity reduced FT to 5% of wild-type enzyme; FT dbSNP:rs199476339). FT /FTId=VAR_054164. FT VARIANT 29 29 D -> N (in MLD; infantile-onset; causes a FT severe reduction of enzyme activity; FT dbSNP:rs199476346). FT /FTId=VAR_054165. FT VARIANT 30 30 D -> H (in MLD; enzyme activity reduced FT to 2.4% of wild-type enzyme; FT dbSNP:rs199476340). FT /FTId=VAR_054166. FT VARIANT 32 32 G -> S (in MLD; late-infantile form; FT dbSNP:rs199476350). FT /FTId=VAR_054167. FT VARIANT 52 52 L -> P (in MLD; loss of enzymatic FT activity; dbSNP:rs199476357). FT /FTId=VAR_067414. FT VARIANT 68 68 L -> P (in MLD; late-infantile form; FT dbSNP:rs199476351). FT /FTId=VAR_054168. FT VARIANT 76 76 L -> P (in dbSNP:rs199476362). FT /FTId=VAR_007243. FT VARIANT 82 82 P -> L (in MLD; late-infantile-onset; FT dbSNP:rs6151411). FT /FTId=VAR_007244. FT VARIANT 84 84 R -> Q (in MLD; mild; dbSNP:rs74315458). FT /FTId=VAR_007245. FT VARIANT 84 84 R -> W (in MLD; juvenile form; FT dbSNP:rs199476352). FT /FTId=VAR_054169. FT VARIANT 86 86 G -> D (in MLD; severe; no enzyme FT residual activity; leads to a decreased FT stability of the mutant enzyme; causes an FT arrest of the mutant enzyme polypeptide FT in a prelysosomal compartment; FT dbSNP:rs74315460). FT /FTId=VAR_007246. FT VARIANT 94 94 P -> A (in MLD; adult form; FT dbSNP:rs199476353). FT /FTId=VAR_054170. FT VARIANT 95 95 S -> N (in MLD; dbSNP:rs199476363). FT /FTId=VAR_007247. FT VARIANT 96 96 S -> F (in MLD; severe; FT dbSNP:rs74315456). FT /FTId=VAR_007248. FT VARIANT 96 96 S -> L (in MLD; severe; no enzyme FT residual activity; dbSNP:rs199476371). FT /FTId=VAR_007249. FT VARIANT 99 99 G -> D (in MLD; adult type; FT dbSNP:rs74315455). FT /FTId=VAR_007250. FT VARIANT 99 99 G -> V (in MLD; late-infantile form; FT dbSNP:rs74315455). FT /FTId=VAR_054171. FT VARIANT 119 119 G -> R (in MLD; juvenile-onset; FT dbSNP:rs199476364). FT /FTId=VAR_007251. FT VARIANT 122 122 G -> S (in MLD; adult type; rs74315461). FT /FTId=VAR_007252. FT VARIANT 135 135 L -> P (in MLD; dbSNP:rs121434215). FT /FTId=VAR_007253. FT VARIANT 136 136 P -> L (in MLD; severe late-infantile FT type; loss of enzymatic activity; FT dbSNP:rs74315462). FT /FTId=VAR_007254. FT VARIANT 136 136 P -> S (in MLD; late-infantile form; FT dbSNP:rs60504011). FT /FTId=VAR_054172. FT VARIANT 137 137 Missing (in MLD). FT /FTId=VAR_054173. FT VARIANT 138 138 H -> D (in MLD; significantly lower FT activity than wild-type protein; FT dbSNP:rs199476358). FT /FTId=VAR_067415. FT VARIANT 143 143 R -> G (in MLD; juvenile/adult-onset; FT generates 5% as much activity as the FT parallel normal control; FT dbSNP:rs199476373). FT /FTId=VAR_054174. FT VARIANT 148 148 P -> L (in MLD; juvenile-onset; FT dbSNP:rs199476375). FT /FTId=VAR_054175. FT VARIANT 152 152 D -> Y (in MLD; dbSNP:rs199476365). FT /FTId=VAR_007255. FT VARIANT 153 153 Q -> H (in MLD; late-infantile form; no FT enzyme residual activity; FT dbSNP:rs199476377). FT /FTId=VAR_054176. FT VARIANT 154 154 G -> D (in MLD; dbSNP:rs74315463). FT /FTId=VAR_007256. FT VARIANT 155 155 P -> L (in MLD; juvenile-onset; FT dbSNP:rs74315464). FT /FTId=VAR_054177. FT VARIANT 155 155 P -> R (in MLD; dbSNP:rs74315464). FT /FTId=VAR_007257. FT VARIANT 156 156 C -> R (in MLD; adult type; enzyme FT activity reduced to 50% of wild-type FT enzyme; dbSNP:rs199476348). FT /FTId=VAR_054178. FT VARIANT 167 167 P -> R (in MLD; dbSNP:rs74315465). FT /FTId=VAR_007258. FT VARIANT 169 169 D -> N (in MLD; dbSNP:rs74315466). FT /FTId=VAR_007259. FT VARIANT 172 172 C -> Y (in MLD; juvenile-onset; FT dbSNP:rs199476381). FT /FTId=VAR_007260. FT VARIANT 179 179 I -> S (in MLD; mild; dbSNP:rs74315457). FT /FTId=VAR_007261. FT VARIANT 181 181 L -> Q (in MLD; infantile form; FT dbSNP:rs199476378). FT /FTId=VAR_054179. FT VARIANT 190 190 Q -> H (in MLD; no enzyme residual FT activity; dbSNP:rs199476372). FT /FTId=VAR_054180. FT VARIANT 191 191 P -> T (in MLD; juvenile-onset; FT dbSNP:rs199476374). FT /FTId=VAR_054181. FT VARIANT 193 193 W -> C (in dbSNP:rs6151415). FT /FTId=VAR_007262. FT VARIANT 201 201 Y -> C (in MLD; juvenile-onset; results FT in higly reduced enzyme activity and FT stability; the mutant enzyme is kept in a FT prelysosomal compartment; FT dbSNP:rs199476345). FT /FTId=VAR_007263. FT VARIANT 212 212 A -> P (in MLD; loss of enzymatic FT activity; dbSNP:rs199476341). FT /FTId=VAR_054182. FT VARIANT 212 212 A -> V (in MLD; dbSNP:rs74315467). FT /FTId=VAR_007264. FT VARIANT 217 217 R -> H (in MLD; enzyme activity reduced FT to 15.6% of wild-type enzyme; FT dbSNP:rs148403406). FT /FTId=VAR_054183. FT VARIANT 219 219 F -> V (in MLD; enzyme activity reduced FT to less than 1% of normal activity; FT dbSNP:rs199476383). FT /FTId=VAR_054184. FT VARIANT 224 224 A -> V (in MLD; dbSNP:rs74315468). FT /FTId=VAR_007265. FT VARIANT 227 227 H -> Y (in MLD; late-infantile form; FT dbSNP:rs199476354). FT /FTId=VAR_054185. FT VARIANT 231 231 P -> T (in MLD; dbSNP:rs74315469). FT /FTId=VAR_007266. FT VARIANT 244 244 R -> C (in MLD; juvenile-onset; FT dbSNP:rs74315470). FT /FTId=VAR_007267. FT VARIANT 244 244 R -> H (in MLD; infantile-onset; FT dbSNP:rs199476366). FT /FTId=VAR_007268. FT VARIANT 245 245 G -> R (in MLD; severe; FT dbSNP:rs74315471). FT /FTId=VAR_007269. FT VARIANT 247 247 F -> S (in MLD; dbSNP:rs199476384). FT /FTId=VAR_054186. FT VARIANT 250 250 S -> Y (in MLD; infantile-onset; FT dbSNP:rs199476367). FT /FTId=VAR_007270. FT VARIANT 253 253 E -> K (in MLD; late-infantile; FT dbSNP:rs74315483). FT /FTId=VAR_054187. FT VARIANT 255 255 D -> H (in MLD; late-infantile form; no FT enzyme residual activity; leads to a FT decreased stability of the mutant enzyme; FT causes an arrest of the mutant enzyme FT polypeptide in a prelysosomal FT compartment; dbSNP:rs80338819). FT /FTId=VAR_054188. FT VARIANT 274 274 T -> M (in MLD; severe; 35% of normal FT activity; dbSNP:rs74315472). FT /FTId=VAR_007271. FT VARIANT 281 281 D -> Y (in MLD; dbSNP:rs199476386). FT /FTId=VAR_054189. FT VARIANT 282 282 N -> S (in MLD; enzyme activity reduced FT to 0.6% of wild-type enzyme; FT dbSNP:rs199476342). FT /FTId=VAR_054190. FT VARIANT 286 286 T -> P (in MLD; adult type; FT dbSNP:rs28940894). FT /FTId=VAR_054191. FT VARIANT 288 288 R -> C (in MLD; dbSNP:rs74315473). FT /FTId=VAR_007272. FT VARIANT 288 288 R -> H (in MLD; adult form; FT dbSNP:rs199476355). FT /FTId=VAR_054192. FT VARIANT 293 293 G -> D (in MLD; late-onset; FT dbSNP:rs199476387). FT /FTId=VAR_054193. FT VARIANT 293 293 G -> S (in MLD; adult type; causes a FT severe reduction of enzyme activity; FT dbSNP:rs199476349). FT /FTId=VAR_054194. FT VARIANT 294 294 C -> Y (in MLD; juvenile-onset; causes a FT severe reduction of enzyme activity; FT dbSNP:rs199476347). FT /FTId=VAR_054195. FT VARIANT 295 295 S -> Y (in MLD; severe; FT dbSNP:rs74315474). FT /FTId=VAR_007273. FT VARIANT 298 298 L -> S (in MLD; late-infantile form; FT complete loss of enzyme activity; FT dbSNP:rs199476389). FT /FTId=VAR_054196. FT VARIANT 300 300 C -> F (in MLD; late-infantile-onset; FT enzyme activity reduced to less than 1%; FT the mutant protein is more rapidly FT degraded in lysosomes; strongly FT interferes with the octamerization FT process of the enzyme at low pH; FT dbSNP:rs74315484). FT /FTId=VAR_008132. FT VARIANT 302 302 K -> N (in MLD; enzyme activity reduced FT to 2.8% of wild-type enzyme; FT dbSNP:rs199476343). FT /FTId=VAR_054197. FT VARIANT 304 304 T -> M (in MLD; loss of enzymatic FT activity; dbSNP:rs199476359). FT /FTId=VAR_067416. FT VARIANT 306 306 Y -> H (in MLD; juvenile-onset; FT dbSNP:rs199476379). FT /FTId=VAR_054198. FT VARIANT 307 307 E -> K (in MLD; loss of enzymatic FT activity; dbSNP:rs199476360). FT /FTId=VAR_067417. FT VARIANT 308 308 G -> D (in MLD; late-infantile form; FT dbSNP:rs199476356). FT /FTId=VAR_054199. FT VARIANT 308 308 G -> V (in MLD; late-infantile form; no FT enzyme residual activity; FT dbSNP:rs199476356). FT /FTId=VAR_054200. FT VARIANT 309 309 G -> S (in MLD; severe; 13% of normal FT activity; dbSNP:rs74315459). FT /FTId=VAR_007274. FT VARIANT 311 311 R -> Q (in MLD; juvenile-onset; FT dbSNP:rs199476382). FT /FTId=VAR_007275. FT VARIANT 312 312 E -> D (in MLD; low amounts of residual FT enzyme activity; leads to a decreased FT stability of the mutant enzyme; FT dbSNP:rs199476390). FT /FTId=VAR_054201. FT VARIANT 314 314 A -> T (in MLD; infantile-onset; FT dbSNP:rs199476368). FT /FTId=VAR_007276. FT VARIANT 325 325 G -> S (in MLD; juvenile-onset; FT dbSNP:rs148092995). FT /FTId=VAR_054202. FT VARIANT 327 327 T -> I (in MLD; late-infantile form). FT /FTId=VAR_054203. FT VARIANT 335 335 D -> V (in MLD; late-infantile-onset; FT loss of enzymatic activity; FT dbSNP:rs74315475). FT /FTId=VAR_007277. FT VARIANT 350 350 N -> S (associated with arylsulfatase A FT pseudodeficiency; appears to be FT responsible for the small size of the FT enzyme produced by pseudodeficiency FT fibroblasts because it leads to loss of FT an N-glycosylation site; FT dbSNP:rs2071421). FT /FTId=VAR_007278. FT VARIANT 356 356 F -> V (in dbSNP:rs6151422). FT /FTId=VAR_018838. FT VARIANT 367 367 K -> N (in MLD; dbSNP:rs199476369). FT /FTId=VAR_007279. FT VARIANT 370 370 R -> Q (in MLD; mild; dbSNP:rs74315477). FT /FTId=VAR_007280. FT VARIANT 370 370 R -> W (in MLD; severe; no enzyme FT residual activity; dbSNP:rs74315476). FT /FTId=VAR_007281. FT VARIANT 376 376 Y -> N (in MLD; enzyme activity reduced FT to 4.7% of wild-type enzyme; FT dbSNP:rs199476344). FT /FTId=VAR_054204. FT VARIANT 377 377 P -> L (in MLD; severe; FT dbSNP:rs74315478). FT /FTId=VAR_007282. FT VARIANT 381 381 D -> E (in MLD; early-infantile form; FT dbSNP:rs6151425). FT /FTId=VAR_054205. FT VARIANT 382 382 E -> K (in MLD; intermediate; FT dbSNP:rs74315479). FT /FTId=VAR_007283. FT VARIANT 384 384 R -> C (in MLD; dbSNP:rs199476370). FT /FTId=VAR_007284. FT VARIANT 390 390 R -> Q (in MLD; juvenile-onset; FT dbSNP:rs199476391). FT /FTId=VAR_007285. FT VARIANT 390 390 R -> W (in MLD; late-infantile and FT juvenile-onset; dbSNP:rs74315480). FT /FTId=VAR_007286. FT VARIANT 391 391 T -> S (in dbSNP:rs743616). FT /FTId=VAR_007287. FT VARIANT 397 397 H -> Y (in MLD; adult-onset; FT dbSNP:rs199476376). FT /FTId=VAR_007288. FT VARIANT 398 398 Missing (in MLD). FT /FTId=VAR_007289. FT VARIANT 406 408 Missing (in MLD; late-infantile-onset). FT /FTId=VAR_007290. FT VARIANT 406 406 S -> G (in MLD; loss of enzymatic FT activity; dbSNP:rs199476361). FT /FTId=VAR_067418. FT VARIANT 408 408 T -> I (in MLD; adult type; FT dbSNP:rs28940895). FT /FTId=VAR_054206. FT VARIANT 409 409 T -> I (in MLD; mild; dbSNP:rs74315481). FT /FTId=VAR_054207. FT VARIANT 425 425 P -> T (in MLD; juvenile-onset; retains FT about 12% of specific enzyme activity; FT the mutant protein is unstable; results FT in more rapid enzyme degradation in FT lysosomes; addition of the cysteine FT protease inhibitor leupeptin increases FT the amount of the enzyme activity; FT displays a modest reduction in the FT octamerization process of the enzyme at FT low pH; dbSNP:rs74315485). FT /FTId=VAR_008133. FT VARIANT 426 426 P -> L (in MLD; juvenile/adult-onset; FT mild; common mutation; dbSNP:rs28940893). FT /FTId=VAR_007291. FT VARIANT 428 428 L -> P (in MLD; late-infantile form; FT dbSNP:rs199476392). FT /FTId=VAR_054208. FT VARIANT 429 429 Y -> S (in MLD; adult-onset; FT dbSNP:rs199476380). FT /FTId=VAR_054209. FT VARIANT 440 440 N -> S (in dbSNP:rs6151427). FT /FTId=VAR_018839. FT VARIANT 464 464 A -> V. FT /FTId=VAR_007292. FT VARIANT 469 469 A -> G (in MLD; early-infantile form; FT dbSNP:rs199476385). FT /FTId=VAR_054210. FT VARIANT 489 489 C -> G (in MLD; late-onset; FT dbSNP:rs199476388). FT /FTId=VAR_054211. FT VARIANT 496 496 R -> H (in dbSNP:rs6151428). FT /FTId=VAR_007293. FT MUTAGEN 69 69 C->A: Abolishes enzyme activity. FT MUTAGEN 69 69 C->S: Strongly decreases enzyme activity. FT CONFLICT 290 290 S -> P (in Ref. 5; AK098659). FT STRAND 22 30 FT HELIX 37 39 FT HELIX 47 54 FT STRAND 56 63 FT STRAND 65 68 FT HELIX 69 78 FT HELIX 82 85 FT HELIX 107 112 FT TURN 113 115 FT STRAND 117 122 FT HELIX 130 132 FT HELIX 136 139 FT STRAND 142 146 FT STRAND 153 155 FT STRAND 159 162 FT TURN 163 165 FT STRAND 181 183 FT STRAND 186 191 FT HELIX 194 196 FT HELIX 197 214 FT STRAND 219 224 FT STRAND 229 231 FT TURN 236 241 FT STRAND 242 244 FT HELIX 245 267 FT HELIX 271 273 FT STRAND 274 282 FT HELIX 286 291 FT STRAND 304 306 FT HELIX 307 310 FT STRAND 315 317 FT TURN 319 321 FT STRAND 324 327 FT HELIX 333 335 FT HELIX 336 343 FT HELIX 359 363 FT STRAND 372 375 FT TURN 382 384 FT STRAND 387 391 FT STRAND 394 400 FT HELIX 404 406 FT STRAND 408 410 FT HELIX 412 414 FT STRAND 421 430 FT TURN 431 433 FT HELIX 450 469 FT HELIX 477 479 FT HELIX 483 485 FT TURN 496 499 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 //