ID ASM_HUMAN STANDARD; PRT; 629 AA. AC P17405; P17406; Q13811; Q16837; Q16841; DT 01-AUG-1990 (Rel. 15, Created) DT 16-OCT-2001 (Rel. 40, Last sequence update) DT 15-MAR-2004 (Rel. 43, Last annotation update) DE Sphingomyelin phosphodiesterase precursor (EC 3.1.4.12) (Acid DE sphingomyelinase) (aSMase). GN SMPD1 OR ASM. OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Primates; Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP SEQUENCE FROM N.A., AND ALTERNATIVE SPLICING. RX MEDLINE=91217097; PubMed=1840600; RA Schuchman E.H., Suchi M., Takahashi T., Sandhoff K., Desnick R.J.; RT "Human acid sphingomyelinase. Isolation, nucleotide sequence and RT expression of the full-length and alternatively spliced cDNAs."; RL J. Biol. Chem. 266:8531-8539(1991). RN [2] RP SEQUENCE FROM N.A. RX MEDLINE=93183402; PubMed=1292508; RA Newrzella D., Stoffel W.; RT "Molecular cloning of the acid sphingomyelinase of the mouse and the RT organization and complete nucleotide sequence of the gene."; RL Biol. Chem. Hoppe-Seyler 373:1233-1238(1992). RN [3] RP SEQUENCE FROM N.A. RX MEDLINE=92155708; PubMed=1740330; RA Schuchman E.H., Levran O., Pereira L.V., Desnick R.J.; RT "Structural organization and complete nucleotide sequence of the gene RT encoding human acid sphingomyelinase (SMPD1)."; RL Genomics 12:197-205(1992). RN [4] RP SEQUENCE FROM N.A., AND VARIANT ARG-157. RX MEDLINE=94012573; PubMed=8407868; RA Ida H., Rennert O.M., Eto Y., Chan W.Y.; RT "Cloning of a human acid sphingomyelinase cDNA with a new mutation RT that renders the enzyme inactive."; RL J. Biochem. 114:15-20(1993). RN [5] RP SEQUENCE OF 128-629 FROM N.A., PARTIAL SEQUENCE, AND RP ALTERNATIVE SPLICING. RC TISSUE=Fibroblast; RX MEDLINE=90060003; PubMed=2555181; RA Quintern L.E., Schuchman E.H., Levran O., Suchi M., Ferlinz K., RA Reinke H., Sandhoff K., Desnick R.J.; RT "Isolation of cDNA clones encoding human acid sphingomyelinase: RT occurrence of alternatively processed transcripts."; RL EMBO J. 8:2469-2473(1989). RN [6] RP CARBOHYDRATE-LINKAGE SITES. RX MEDLINE=97182640; PubMed=9030779; RA Ferlinz K., Hurwitz R., Moczall H., Lansmann S., Schuchman E.H., RA Sandhoff K.; RT "Functional characterization of the N-glycosylation sites of human RT acid sphingomyelinase by site-directed mutagenesis."; RL Eur. J. Biochem. 243:511-517(1997). RN [7] RP DISULFIDE BONDS. RX MEDLINE=22518502; PubMed=12631268; RA Lansmann S., Schuette C.G., Bartelsen O., Hoernschemeyer J., Linke T., RA Weisgerber J., Sandhoff K.; RT "Human acid sphingomyelinase."; RL Eur. J. Biochem. 270:1076-1088(2003). RN [8] RP VARIANT NPA SER-577. RX MEDLINE=92028849; PubMed=1718266; RA Ferlinz K., Hurwitz R., Sandhoff K.; RT "Molecular basis of acid sphingomyelinase deficiency in a patient RT with Niemann-Pick disease type A."; RL Biochem. Biophys. Res. Commun. 179:1187-1191(1991). RN [9] RP VARIANT NPA LEU-496. RX MEDLINE=91219449; PubMed=2023926; RA Levran O., Desnick R.J., Schuchman E.H.; RT "Niemann-Pick disease: a frequent missense mutation in the acid RT sphingomyelinase gene of Ashkenazi Jewish type A and B patients."; RL Proc. Natl. Acad. Sci. U.S.A. 88:3748-3752(1991). RN [10] RP VARIANT NPB ARG-608 DEL. RX MEDLINE=91358737; PubMed=1885770; RA Levran O., Desnick R.J., Schuchman E.H.; RT "Niemann-Pick type B disease. Identification of a single codon RT deletion in the acid sphingomyelinase gene and genotype/phenotype RT correlations in type A and B patients."; RL J. Clin. Invest. 88:806-810(1991). RN [11] RP VARIANT NPA PRO-302. RX MEDLINE=93004773; PubMed=1391960; RA Levran O., Desnick R.J., Schuchman E.H.; RT "Identification and expression of a common missense mutation (L302P) RT in the acid sphingomyelinase gene of Ashkenazi Jewish type A RT Niemann-Pick disease patients."; RL Blood 80:2081-2087(1992). RN [12] RP VARIANT NPB ARG-436. RX MEDLINE=93244834; PubMed=1301192; RA Takahashi T., Desnick R.J., Takada G., Schuchman E.H.; RT "Identification of a missense mutation (S436R) in the acid RT sphingomyelinase gene from a Japanese patient with type B RT Niemann-Pick disease."; RL Hum. Mutat. 1:70-71(1992). RN [13] RP VARIANT NPA ILE-382, AND VARIANTS NPB ARG-242 AND SER-383. RX MEDLINE=92316934; PubMed=1618760; RA Takahashi T., Suchi M., Desnick R.J., Takada G., Schuchman E.H.; RT "Identification and expression of five mutations in the human acid RT sphingomyelinase gene causing types A and B Niemann-Pick disease. RT Molecular evidence for genetic heterogeneity in the neuronopathic and RT non-neuronopathic forms."; RL J. Biol. Chem. 267:12552-12558(1992). RN [14] RP VARIANT NPB GLY-391. RX MEDLINE=94328611; PubMed=8051942; RA Sperl W., Bart G., Vanier M.T., Christomanou H., Baldissera I., RA Steichensdorf E., Paschke E.; RT "A family with visceral course of Niemann-Pick disease, macular halo RT syndrome and low sphingomyelin degradation rate."; RL J. Inherit. Metab. Dis. 17:93-103(1994). RN [15] RP VARIANT NPA THR-389. RX MEDLINE=96287387; PubMed=8680412; RA Schuchman E.H.; RT "Two new mutations in the acid sphingomyelinase gene causing type A RT Niemann-pick disease: N389T and R441X."; RL Hum. Mutat. 6:352-354(1995). RN [16] RP VARIANT NPA CYS-446. RX MEDLINE=96274768; PubMed=8693491; RA Takahashi T., Suchi M., Sato W., Ten S.B., Sakuragawa N., RA Desnick R.J., Schuchman E.H., Takada G.; RT "Identification and expression of a missense mutation (Y446C) in the RT acid sphingomyelinase gene from a Japanese patient with type A RT Niemann-Pick disease."; RL Tohoku J. Exp. Med. 177:117-123(1995). RN [17] RP VARIANT NPA GLN-246. RX MEDLINE=96263741; PubMed=8664904; RA Ida H., Rennert O.M., Maekawa K., Eto Y.; RT "Identification of three novel mutations in the acid RT sphingomyelinase gene of Japanese patients with Niemann-Pick disease RT type A and B."; RL Hum. Mutat. 7:65-67(1996). RN [18] RP VARIANT NPB TYR-421. RX MEDLINE=22340429; PubMed=12369017; RA Simonaro C.M., Desnick R.J., McGovern M.M., Wasserstein M.P., RA Schuchman E.H.; RT "The demographics and distribution of type B Niemann-Pick disease: RT novel mutations lead to new genotype/phenotype correlations."; RL Am. J. Hum. Genet. 71:1413-1419(2002). RN [19] RP VARIANTS NPA ARG-248; TYR-319; SER-463; LEU-475 AND HIS-537, AND RP VARIANTS NPB SER-371 AND ARG-608 DEL. RX MEDLINE=22444008; PubMed=12556236; RA Sikora J., Pavlu-Pereira H., Elleder M., Roelofs H., Wevers R.A.; RT "Seven novel Acid sphingomyelinase gene mutations in Niemann-Pick type RT A and B patients."; RL Ann. Hum. Genet. 67:63-70(2003). CC -!- FUNCTION: Converts sphingomyelin to ceramide. aSM also has CC phospholipase C activities toward 1,2-diacylglycerolphosphocholine CC and 1,2-diacylglycerolphosphoglycerol. CC -!- CATALYTIC ACTIVITY: Sphingomyelin + H(2)O = N-acylsphingosine + CC choline phosphate. CC -!- SUBUNIT: Monomer. CC -!- SUBCELLULAR LOCATION: Lysosomal. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=ASM-1; CC IsoId=P17405-1; Sequence=Displayed; CC Name=2; Synonyms=ASM-2; CC IsoId=P17405-2; Sequence=VSP_000331, VSP_000332; CC Name=3; Synonyms=ASM-3; CC IsoId=P17405-3; Sequence=VSP_000333; CC -!- DISEASE: Defects in SMPD1 are the cause of Niemann-Pick disease CC type A (NPA) [MIM:257200]; also referred to as the classical CC infantile form. Niemann-Pick disease is a clinically and CC genetically heterogeneous recessive disorder. It is caused by the CC accumulation of sphingomyelin and other metabolically related CC lipids in the lysosomes, resulting in neurodegeneration starting CC from early life. Patients may show xanthomas, pigmentation, CC hepatosplenomegaly, lymphadenopathy and mental retardation. CC Niemann-Pick disease occurs more frequently among individuals of CC Ashkenazi Jewish ancestry than in the general population. NPA is CC characterized by very early onset in infancy and a rapidly CC progressive course leading to death by three years. CC -!- DISEASE: Defects in SMPD1 are the cause of Niemann-Pick disease CC type B (NPB) [MIM:607616]; also referred to as the visceral form. CC NPB has little if any neurologic involvement and patients may CC survive into adulthood. CC -!- MISCELLANEOUS: There are two types of sphingomyelinases: ASM CC (acid), and NSM (neutral). CC -!- MISCELLANEOUS: Isoform 1 is the most abundant (90%), isoforms 2 CC (10%) and 3 (<1%) are only found at lower levels. Only isoform 1 CC is a catalytic active enzyme. CC -!- SIMILARITY: Belongs to the acid sphingomyelinase family. CC -!- SIMILARITY: Contains 1 saposin B-type domain. CC -------------------------------------------------------------------------- CC This SWISS-PROT entry is copyright. It is produced through a collaboration CC between the Swiss Institute of Bioinformatics and the EMBL outstation - CC the European Bioinformatics Institute. There are no restrictions on its CC use by non-profit institutions as long as its content is in no way CC modified and this statement is not removed. Usage by and for commercial CC entities requires a license agreement (See http://www.isb-sib.ch/announce/ CC or send an email to license@isb-sib.ch). CC -------------------------------------------------------------------------- DR EMBL; M59916; AAA58377.1; -. DR EMBL; M59917; AAA58378.1; -. DR EMBL; X63600; CAA45145.1; -. DR EMBL; X52678; CAA36901.1; -. DR EMBL; X52679; CAA36902.1; -. DR EMBL; M81780; AAA75008.1; -. DR EMBL; M81780; AAA75009.1; -. DR EMBL; X59960; CAA42584.1; -. DR PIR; S06958; S06958. DR PIR; S27009; A39825. DR Genew; HGNC:11120; SMPD1. DR MIM; 607608; -. DR MIM; 257200; -. DR MIM; 607616; -. DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; TAS. DR GO; GO:0007399; P:neurogenesis; TAS. DR GO; GO:0007165; P:signal transduction; TAS. DR GO; GO:0006684; P:sphingomyelin metabolism; TAS. DR InterPro; IPR004843; M-ppestrase. DR InterPro; IPR008139; SaposinB. DR Pfam; PF00149; Metallophos; 1. DR SMART; SM00118; SAPB; 1. KW Hydrolase; Glycosidase; Lysosome; Glycoprotein; Alternative splicing; KW Signal; Disease mutation. FT SIGNAL 1 46 FT CHAIN 47 629 Sphingomyelin phosphodiesterase. FT DOMAIN 85 169 Saposin-like type B. FT DISULFID 120 131 FT DISULFID 221 226 FT DISULFID 227 250 FT DISULFID 385 431 FT DISULFID 584 588 FT DISULFID 594 607 FT CARBOHYD 86 86 N-linked (GlcNAc...). FT CARBOHYD 175 175 N-linked (GlcNAc...). FT CARBOHYD 335 335 N-linked (GlcNAc...). FT CARBOHYD 395 395 N-linked (GlcNAc...). FT CARBOHYD 520 520 N-linked (GlcNAc...). FT VARSPLIC 363 374 IGGFYALSPYPG -> YLSSVETQEGKR (in isoform FT 2). FT /FTId=VSP_000331. FT VARSPLIC 375 418 Missing (in isoform 2). FT /FTId=VSP_000332. FT VARSPLIC 363 418 Missing (in isoform 3). FT /FTId=VSP_000333. FT VARIANT 157 157 C -> R (Seems to be less active). FT /FTId=VAR_011387. FT VARIANT 242 242 G -> R (in NPB). FT /FTId=VAR_005058. FT VARIANT 246 246 E -> Q (in NPA; 30% residual FT activity). FT /FTId=VAR_005059. FT VARIANT 248 248 S -> R (in NPA). FT /FTId=VAR_015287. FT VARIANT 302 302 L -> P (in NPA; in 23% of NPA Ashkenazi FT Jewish patients). FT /FTId=VAR_005060. FT VARIANT 319 319 H -> Y (in NPA). FT /FTId=VAR_015288. FT VARIANT 371 371 P -> S (in NPB). FT /FTId=VAR_015289. FT VARIANT 382 382 M -> I (in NPA). FT /FTId=VAR_005061. FT VARIANT 383 383 N -> S (in NPB). FT /FTId=VAR_005062. FT VARIANT 389 389 N -> T (in NPA). FT /FTId=VAR_005063. FT VARIANT 391 391 W -> G (in NPB; low sphingomyelin FT degradation rates). FT /FTId=VAR_005064. FT VARIANT 421 421 H -> Y (in NPB). FT /FTId=VAR_015290. FT VARIANT 436 436 S -> R (in NPB). FT /FTId=VAR_005065. FT VARIANT 446 446 Y -> C (in NPA). FT /FTId=VAR_011388. FT VARIANT 463 463 F -> S (in NPA). FT /FTId=VAR_015291. FT VARIANT 475 475 P -> L (in NPA). FT /FTId=VAR_015292. FT VARIANT 496 496 R -> L (in NPA; in 32% of NPA Ashkenazi FT Jewish patients). FT /FTId=VAR_005066. FT VARIANT 537 537 Y -> H (in NPA). FT /FTId=VAR_015293. FT VARIANT 577 577 G -> S (in NPA). FT /FTId=VAR_005067. FT VARIANT 608 608 Missing (in NPB; prevalent among NPB FT patients from the North-African Maghreb FT region). FT /FTId=VAR_005068. FT CONFLICT 35 36 Missing (in Ref. 4). FT CONFLICT 36 36 V -> A (in Ref. 3). FT CONFLICT 322 322 T -> I (in Ref. 1). FT CONFLICT 506 506 R -> G (in Ref. 3 and 4). SQ SEQUENCE 629 AA; 69851 MW; C994FCB1458942AC CRC64; MPRYGASLRQ SCPRSGREQG QDGTAGAPGL LWMGLVLALA LALALALSDS RVLWAPAEAH PLSPQGHPAR LHRIVPRLRD VFGWGNLTCP ICKGLFTAIN LGLKKEPNVA RVGSVAIKLC NLLKIAPPAV CQSIVHLFED DMVEVWRRSV LSPSEACGLL LGSTCGHWDI FSSWNISLPT VPKPPPKPPS PPAPGAPVSR ILFLTDLHWD HDYLEGTDPD CADPLCCRRG SGLPPASRPG AGYWGEYSKC DLPLRTLESL LSGLGPAGPF DMVYWTGDIP AHDVWHQTRQ DQLRALTTVT ALVRKFLGPV PVYPAVGNHE STPVNSFPPP FIEGNHSSRW LYEAMAKAWE PWLPAEALRT LRIGGFYALS PYPGLRLISL NMNFCSRENF WLLINSTDPA GQLQWLVGEL QAAEDRGDKV HIIGHIPPGH CLKSWSWNYY RIVARYENTL AAQFFGHTHV DEFEVFYDEE TLSRPLAVAF LAPSATTYIG LNPGYRVYQI DGNYSRSSHV VLDHETYILN LTQANIPGAI PHWQLLYRAR ETYGLPNTLP TAWHNLVYRM RGDMQLFQTF WFLYHKGHPP SEPCGTPCRL ATLCAQLSAR ADSPALCRHL MPDGSLPEAQ SLWPRPLFC //