RBCC

Full text data of SPAST

SPAST (ADPSP, FSP2, KIAA1083, SPG4) [Confidence: low (only semi-automatic identification from reviews)]
Spastin; 3.6.4.3 (Spastic paraplegia 4 protein)

UniProt Q9UBP0
ID SPAST_HUMAN Reviewed; 616 AA.
AC Q9UBP0; A7E2A7; Q9UPR9;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Spastin;
DE EC=3.6.4.3;
DE AltName: Full=Spastic paraplegia 4 protein;
GN Name=SPAST; Synonyms=ADPSP, FSP2, KIAA1083, SPG4;
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 [GENOMIC DNA / MRNA] (ISOFORM 1), TISSUE
RP SPECIFICITY, DEVELOPMENTAL STAGE, AND VARIANTS SPG4 CYS-362; TYR-448
RP AND CYS-499.
RX PubMed=10610178; DOI=10.1038/15472;
RA Hazan J., Fonknechten N., Mavel D., Paternotte C., Samson D.,
RA Artiguenave F., Davoine C.-S., Cruaud C., Durr A., Wincker P.,
RA Brottier P., Cattolico L., Barbe V., Burgunder J.-M.,
RA Prud'homme J.-F., Brice A., Fontaine B., Heilig R., Weissenbach J.;
RT "Spastin, a new AAA protein, is altered in the most frequent form of
RT autosomal dominant spastic paraplegia.";
RL Nat. Genet. 23:296-303(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=10470851; DOI=10.1093/dnares/6.3.197;
RA Kikuno R., Nagase T., Ishikawa K., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIV.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 6:197-205(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 [5]
RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS SPG4
RP ARG-370; CYS-381; LYS-386; ARG-388; VAL-426; TYR-448; LEU-460; CYS-499
RP AND VAL-556.
RX PubMed=11809724; DOI=10.1093/hmg/11.2.153;
RA Errico A., Ballabio A., Rugarli E.I.;
RT "Spastin, the protein mutated in autosomal dominant hereditary spastic
RT paraplegia, is involved in microtubule dynamics.";
RL Hum. Mol. Genet. 11:153-163(2002).
RN [6]
RP DOMAIN MIT, AND PROBABLE FUNCTION.
RX PubMed=12676568; DOI=10.1016/S0888-7543(03)00011-9;
RA Ciccarelli F.D., Proukakis C., Patel H., Cross H., Azam S.,
RA Patton M.A., Bork P., Crosby A.H.;
RT "The identification of a conserved domain in both spartin and spastin,
RT mutated in hereditary spastic paraplegia.";
RL Genomics 81:437-441(2003).
RN [7]
RP SUBCELLULAR LOCATION, AND NUCLEAR LOCALIZATION SIGNAL.
RX PubMed=15147984; DOI=10.1016/j.bbrc.2004.03.195;
RA Beetz C., Brodhun M., Moutzouris K., Kiehntopf M., Berndt A.,
RA Lehnert D., Deufel T., Bastmeyer M., Schickel J.;
RT "Identification of nuclear localisation sequences in spastin (SPG4)
RT using a novel Tetra-GFP reporter system.";
RL Biochem. Biophys. Res. Commun. 318:1079-1084(2004).
RN [8]
RP INTERACTION WITH SSNA1 AND MICROTUBULES, AND SUBCELLULAR LOCATION.
RX PubMed=15269182; DOI=10.1093/hmg/ddh223;
RA Errico A., Claudiani P., D'Addio M., Rugarli E.I.;
RT "Spastin interacts with the centrosomal protein NA14, and is enriched
RT in the spindle pole, the midbody and the distal axon.";
RL Hum. Mol. Genet. 13:2121-2132(2004).
RN [9]
RP ALTERNATIVE INITIATION, SUBCELLULAR LOCATION, NUCLEAR EXPORT SIGNALS,
RP AND MUTAGENESIS OF MET-1 AND MET-87.
RX PubMed=16026783; DOI=10.1016/j.yexcr.2005.06.009;
RA Claudiani P., Riano E., Errico A., Andolfi G., Rugarli E.I.;
RT "Spastin subcellular localization is regulated through usage of
RT different translation start sites and active export from the
RT nucleus.";
RL Exp. Cell Res. 309:358-369(2005).
RN [10]
RP INTERACTION WITH CHMP1B, AND SUBCELLULAR LOCATION.
RX PubMed=15537668; DOI=10.1093/hmg/ddi003;
RA Reid E., Connell J.W., Edwards T.L., Duley S., Brown S.E.,
RA Sanderson C.M.;
RT "The hereditary spastic paraplegia protein spastin interacts with the
RT ESCRT-III complex-associated endosomal protein CHMP1B.";
RL Hum. Mol. Genet. 14:19-38(2005).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP INTERACTION WITH MICROTUBULES, SUBCELLULAR LOCATION, MUTAGENESIS OF
RP LYS-388 AND GLU-442, AND CHARACTERIZATION OF VARIANTS SPG4 LYS-344;
RP LYS-347; LYS-386; ARG-388 AND CYS-499.
RX PubMed=15716377; DOI=10.1083/jcb.200409058;
RA Evans K.J., Gomes E.R., Reisenweber S.M., Gundersen G.G.,
RA Lauring B.P.;
RT "Linking axonal degeneration to microtubule remodeling by Spastin-
RT mediated microtubule severing.";
RL J. Cell Biol. 168:599-606(2005).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, ASSOCIATION WITH MICROTUBULES, AND
RP SUBCELLULAR LOCATION.
RX PubMed=16219033; DOI=10.1111/j.1471-4159.2005.03472.x;
RA Salinas S., Carazo-Salas R.E., Proukakis C., Cooper J.M., Weston A.E.,
RA Schiavo G., Warner T.T.;
RT "Human spastin has multiple microtubule-related functions.";
RL J. Neurochem. 95:1411-1420(2005).
RN [13]
RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT SPG4 ARG-388.
RX PubMed=15891913; DOI=10.1007/s10048-005-0219-2;
RA Svenson I.K., Kloos M.T., Jacon A., Gallione C., Horton A.C.,
RA Pericak-Vance M.A., Ehlers M.D., Marchuk D.A.;
RT "Subcellular localization of spastin: implications for the
RT pathogenesis of hereditary spastic paraplegia.";
RL Neurogenetics 6:135-141(2005).
RN [14]
RP INTERACTION WITH ZFYVE27.
RX PubMed=16826525; DOI=10.1086/504927;
RA Mannan A.U., Krawen P., Sauter S.M., Boehm J., Chronowska A.,
RA Paulus W., Neesen J., Engel W.;
RT "ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in
RT hereditary spastic paraplegia.";
RL Am. J. Hum. Genet. 79:351-357(2006).
RN [15]
RP INTERACTION WITH ATL1, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF
RP VARIANT SPG4 ARG-388.
RX PubMed=16339213; DOI=10.1093/hmg/ddi447;
RA Sanderson C.M., Connell J.W., Edwards T.L., Bright N.A., Duley S.,
RA Thompson A., Luzio J.P., Reid E.;
RT "Spastin and atlastin, two proteins mutated in autosomal-dominant
RT hereditary spastic paraplegia, are binding partners.";
RL Hum. Mol. Genet. 15:307-318(2006).
RN [16]
RP INTERACTION WITH RTN1, AND SUBCELLULAR LOCATION.
RX PubMed=16602018; DOI=10.1007/s10048-006-0034-4;
RA Mannan A.U., Boehm J., Sauter S.M., Rauber A., Byrne P.C., Neesen J.,
RA Engel W.;
RT "Spastin, the most commonly mutated protein in hereditary spastic
RT paraplegia interacts with Reticulon 1 an endoplasmic reticulum
RT protein.";
RL Neurogenetics 7:93-103(2006).
RN [17]
RP CATALYTIC ACTIVITY, INTERACTION WITH ATL1, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF GLU-442.
RX PubMed=16815977; DOI=10.1073/pnas.0510863103;
RA Evans K.J., Keller C., Pavur K., Glasgow K., Conn B., Lauring B.P.;
RT "Interaction of two hereditary spastic paraplegia gene products,
RT spastin and atlastin, suggests a common pathway for axonal
RT maintenance.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10666-10671(2006).
RN [18]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP HOMOHEXAMERIZATION, INTERACTION WITH TUBULIN AND MICROTUBULES,
RP SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-415; GLU-442; ARG-451 AND
RP ALA-457, AND CHARACTERIZATION OF VARIANT SPG4 TYR-448.
RX PubMed=17389232; DOI=10.1083/jcb.200610072;
RA White S.R., Evans K.J., Lary J., Cole J.L., Lauring B.P.;
RT "Recognition of C-terminal amino acids in tubulin by pore loops in
RT Spastin is important for microtubule severing.";
RL J. Cell Biol. 176:995-1005(2007).
RN [19]
RP ALTERNATIVE PROMOTER USAGE, AND CHARACTERIZATION OF VARIANT LEU-44.
RX PubMed=18613979; DOI=10.1186/1741-7007-6-31;
RA Mancuso G., Rugarli E.I.;
RT "A cryptic promoter in the first exon of the SPG4 gene directs the
RT synthesis of the 60-kDa spastin isoform.";
RL BMC Biol. 6:31-31(2008).
RN [20]
RP CATALYTIC ACTIVITY, HOMOHEXAMERIZATION, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF GLU-442.
RX PubMed=18410514; DOI=10.1111/j.1471-4159.2008.05414.x;
RA Pantakani D.V.K., Swapna L.S., Srinivasan N., Mannan A.U.;
RT "Spastin oligomerizes into a hexamer and the mutant spastin (E442Q)
RT redistribute the wild-type spastin into filamentous microtubule.";
RL J. Neurochem. 106:613-624(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-268 AND THR-306, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-268, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [23]
RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT SPG4
RP ARG-388.
RX PubMed=19000169; DOI=10.1111/j.1600-0854.2008.00847.x;
RA Connell J.W., Lindon C., Luzio J.P., Reid E.;
RT "Spastin couples microtubule severing to membrane traffic in
RT completion of cytokinesis and secretion.";
RL Traffic 10:42-56(2009).
RN [24]
RP INTERACTION WITH REEP1.
RX PubMed=20200447; DOI=10.1172/JCI40979;
RA Park S.H., Zhu P.P., Parker R.L., Blackstone C.;
RT "Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1
RT coordinate microtubule interactions with the tubular ER network.";
RL J. Clin. Invest. 120:1097-1110(2010).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-268, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-245, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [27]
RP HOMOHEXAMERIZATION, FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION,
RP KINETIC STUDIES, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT,
RP COOPERATIVITY, AND MUTAGENESIS OF GLU-442.
RX PubMed=22637577; DOI=10.1074/jbc.M111.291898;
RA Eckert T., Link S., Le D.T., Sobczak J.P., Gieseke A., Richter K.,
RA Woehlke G.;
RT "Subunit Interactions and cooperativity in the microtubule-severing
RT AAA ATPase spastin.";
RL J. Biol. Chem. 287:26278-26290(2012).
RN [28]
RP INTERACTION WITH RTN2.
RX PubMed=22232211; DOI=10.1172/JCI60560;
RA Montenegro G., Rebelo A.P., Connell J., Allison R., Babalini C.,
RA D'Aloia M., Montieri P., Schule R., Ishiura H., Price J.,
RA Strickland A., Gonzalez M.A., Baumbach-Reardon L., Deconinck T.,
RA Huang J., Bernardi G., Vance J.M., Rogers M.T., Tsuji S.,
RA De Jonghe P., Pericak-Vance M.A., Schols L., Orlacchio A., Reid E.,
RA Zuchner S.;
RT "Mutations in the ER-shaping protein reticulon 2 cause the axon-
RT degenerative disorder hereditary spastic paraplegia type 12.";
RL J. Clin. Invest. 122:538-544(2012).
RN [29]
RP INTERACTION WITH MICROTUBULES, OLIGOMERIZATION, AND MUTAGENESIS OF
RP 310-LYS--LYS-312 AND GLU-442.
RX PubMed=23272056; DOI=10.1371/journal.pone.0050161;
RA Eckert T., Le D.T., Link S., Friedmann L., Woehlke G.;
RT "Spastin's microtubule-binding properties and comparison to katanin.";
RL PLoS ONE 7:E50161-E50161(2012).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 112-196 IN COMPLEX WITH
RP CHMP1B, INTERACTION WITH CHMP1B, SUBCELLULAR LOCATION, AND MUTAGENESIS
RP OF HIS-120 AND PHE-124.
RX PubMed=18997780; DOI=10.1038/nsmb.1512;
RA Yang D., Rismanchi N., Renvoise B., Lippincott-Schwartz J.,
RA Blackstone C., Hurley J.H.;
RT "Structural basis for midbody targeting of spastin by the ESCRT-III
RT protein CHMP1B.";
RL Nat. Struct. Mol. Biol. 15:1278-1286(2008).
RN [31]
RP VARIANT SPG4 GLY-441.
RX PubMed=11039577; DOI=10.1038/sj.ejhg.5200528;
RA Buerger J., Fonknechten N., Hoeltzenbein M., Neumann L., Bratanoff E.,
RA Hazan J., Reis A.;
RT "Hereditary spastic paraplegia caused by mutations in the SPG4 gene.";
RL Eur. J. Hum. Genet. 8:771-776(2000).
RN [32]
RP VARIANTS SPG4 CYS-362; ARG-370; CYS-381; LYS-386; ARG-388; VAL-426;
RP TYR-448; LEU-460; CYS-499; ASN-555 AND VAL-556.
RX PubMed=10699187; DOI=10.1093/hmg/9.4.637;
RA Fonknechten N., Mavel D., Byrne P., Davoine C.-S., Cruaud C.,
RA Bonsch D., Samson D., Coutinho P., Hutchinson M., McMonagle P.,
RA Burgunder J.-M., Tartaglione A., Heinzlef O., Feki I., Deufel T.,
RA Parfrey N., Brice A., Fontaine B., Prud'homme J.-F., Weissenbach J.,
RA Duerr A., Hazan J.;
RT "Spectrum of SPG4 mutations in autosomal dominant spastic
RT paraplegia.";
RL Hum. Mol. Genet. 9:637-644(2000).
RN [33]
RP VARIANTS SPG4 LEU-44; GLY-424 AND HIS-584.
RX PubMed=11015453; DOI=10.1136/jmg.37.10.759;
RA Lindsey J.C., Lusher M.E., McDermott C.J., White K.D., Reid E.,
RA Rubinsztein D.C., Bashir R., Hazan J., Shaw P.J., Bushby K.M.D.;
RT "Mutation analysis of the spastin gene (SPG4) in patients with
RT hereditary spastic paraparesis.";
RL J. Med. Genet. 37:759-765(2000).
RN [34]
RP VARIANTS SPG4 PHE-436 AND ASP-559.
RX PubMed=11087788;
RA Hentati A., Deng H.-X., Zhai H., Chen W., Yang Y., Hung W.-Y.,
RA Azim A.C., Bohlega S., Tandan R., Warner C., Laing N.G., Cambi F.,
RA Mitsumoto H., Roos R.P., Boustany R.-M.N., Ben-Hamida M., Hentati F.,
RA Siddique T.;
RT "Novel mutations in spastin gene and absence of correlation with age
RT at onset of symptoms.";
RL Neurology 55:1388-1390(2000).
RN [35]
RP VARIANTS SPG4 CYS-499 AND GLY-562.
RX PubMed=11309678; DOI=10.1086/320111;
RA Svenson I.K., Ashley-Koch A.E., Gaskell P.C., Riney T.J.,
RA Cumming W.J.K., Kingston H.M., Hogan E.L., Boustany R.-M.N.,
RA Vance J.M., Nance M.A., Pericak-Vance M.A., Marchuk D.A.;
RT "Identification and expression analysis of spastin gene mutations in
RT hereditary spastic paraplegia.";
RL Am. J. Hum. Genet. 68:1077-1085(2001).
RN [36]
RP VARIANT SPG4 VAL-485.
RX PubMed=12460147; DOI=10.1034/j.1600-0404.2002.01254.x;
RA Namekawa M., Takiyama Y., Sakoe K., Nagaki H., Shimazaki H.,
RA Yoshimura M., Ikeguchi K., Nakano I., Nishizawa M.;
RT "A Japanese SPG4 family with a novel missense mutation of the SPG4
RT gene: intrafamilial variability in age at onset and clinical
RT severity.";
RL Acta Neurol. Scand. 106:387-391(2002).
RN [37]
RP VARIANTS SPG4 LEU-399; VAL-426; LEU-489; ASP-559 AND GLN-562.
RX PubMed=11843700; DOI=10.1001/archneur.59.2.281;
RA Meijer I.A., Hand C.K., Cossette P., Figlewicz D.A., Rouleau G.A.;
RT "Spectrum of SPG4 mutations in a large collection of North American
RT families with hereditary spastic paraplegia.";
RL Arch. Neurol. 59:281-286(2002).
RN [38]
RP VARIANTS SPG4 ARG-407; TYR-551 AND ILE-615.
RX PubMed=12124993; DOI=10.1002/humu.10105;
RA Sauter S.M., Miterski B., Klimpe S., Boensch D., Schoels L.,
RA Visbeck A., Papke T., Hopf H.C., Engel W., Deufel T., Epplen J.T.,
RA Neesen J.;
RT "Mutation analysis of the spastin gene (SPG4) in patients in Germany
RT with autosomal dominant hereditary spastic paraplegia.";
RL Hum. Mutat. 20:127-132(2002).
RN [39]
RP VARIANTS SPG4 LYS-347; ARG-388 AND CYS-499.
RX PubMed=12161613; DOI=10.1136/jmg.39.8.e46;
RA Yabe I., Sasaki H., Tashiro K., Matsuura T., Takegami T., Satoh T.;
RT "Spastin gene mutation in Japanese with hereditary spastic
RT paraplegia.";
RL J. Med. Genet. 39:E46-E46(2002).
RN [40]
RP VARIANT SPG4 ASP-512.
RX PubMed=11985387; DOI=10.1007/PL00007865;
RA Patrono C., Casali C., Tessa A., Cricchi F., Fortini D., Carrozzo R.,
RA Siciliano G., Bertini E., Santorelli F.M.;
RT "Missense and splice site mutations in SPG4 suggest loss-of-function
RT in dominant spastic paraplegia.";
RL J. Neurol. 249:200-205(2002).
RN [41]
RP VARIANT SPG4 PHE-404 DEL.
RX PubMed=12163196; DOI=10.1016/S0022-510X(02)00192-2;
RA Proukakis C., Hart P.E., Cornish A., Warner T.T., Crosby A.H.;
RT "Three novel spastin (SPG4) mutations in families with autosomal
RT dominant hereditary spastic paraplegia.";
RL J. Neurol. Sci. 201:65-69(2002).
RN [42]
RP VARIANT SPG4 LYS-344.
RX PubMed=12202986; DOI=10.1007/s100380200068;
RA Ki C.S., Lee W.Y., Han do H., Sung D.H., Lee K.B., Lee K.A., Cho S.S.,
RA Cho S., Hwang H., Sohn K.M., Choi Y.J., Kim J.W.;
RT "A novel missense mutation (I344K) in the SPG4gene in a Korean family
RT with autosomal-dominant hereditary spastic paraplegia.";
RL J. Hum. Genet. 47:473-477(2002).
RN [43]
RP VARIANT SPG4 LEU-503.
RX PubMed=12552568; DOI=10.1002/humu.9108;
RA Proukakis C., Auer-Grumbach M., Wagner K., Wilkinson P.A., Reid E.,
RA Patton M.A., Warner T.T., Crosby A.H.;
RT "Screening of patients with hereditary spastic paraplegia reveals
RT seven novel mutations in the SPG4 (Spastin) gene.";
RL Hum. Mutat. 21:170-170(2003).
RN [44]
RP VARIANT SPG4 PRO-534.
RX PubMed=12939659; DOI=10.1038/sj.ejhg.5201027;
RA Molon A., Montagna P., Angelini C., Pegoraro E.;
RT "Novel spastin mutations and their expression analysis in two Italian
RT families.";
RL Eur. J. Hum. Genet. 11:710-713(2003).
RN [45]
RP VARIANTS SPG4 GLN-378; VAL-390 AND LEU-515 DEL.
RX PubMed=14732620; DOI=10.1001/archneur.61.1.49;
RA Tang B., Zhao G., Xia K., Pan Q., Luo W., Shen L., Long Z., Dai H.,
RA Zi X., Jiang H.;
RT "Three novel mutations of the spastin gene in Chinese patients with
RT hereditary spastic paraplegia.";
RL Arch. Neurol. 61:49-55(2004).
RN [46]
RP VARIANT SPG4 SER-386.
RX PubMed=15210521; DOI=10.1001/archneur.61.6.849;
RA Orlacchio A., Kawarai T., Totaro A., Errico A., St George-Hyslop P.H.,
RA Rugarli E.I., Bernardi G.;
RT "Hereditary spastic paraplegia: clinical genetic study of 15
RT families.";
RL Arch. Neurol. 61:849-855(2004).
RN [47]
RP VARIANTS SPG4 VAL-470 AND GLY-562, AND VARIANTS LEU-44 AND GLN-45.
RX PubMed=15248095; DOI=10.1007/s10048-004-0186-z;
RA Svenson I.K., Kloos M.T., Gaskell P.C., Nance M.A., Garbern J.Y.,
RA Hisanaga S., Pericak-Vance M.A., Ashley-Koch A.E., Marchuk D.A.;
RT "Intragenic modifiers of hereditary spastic paraplegia due to spastin
RT gene mutations.";
RL Neurogenetics 5:157-164(2004).
RN [48]
RP VARIANTS SPG4 GLY-459 AND CYS-460.
RX PubMed=15482961; DOI=10.1016/j.nmd.2004.05.017;
RA Falco M., Scuderi C., Musumeci S., Sturnio M., Neri M., Bigoni S.,
RA Caniatti L., Fichera M.;
RT "Two novel mutations in the spastin gene (SPG4) found by DHPLC
RT mutation analysis.";
RL Neuromuscul. Disord. 14:750-753(2004).
RN [49]
RP VARIANT SPG4 ILE-614.
RX PubMed=15159500;
RA Orlacchio A., Gaudiello F., Totaro A., Floris R.,
RA St George-Hyslop P.H., Bernardi G., Kawarai T.;
RT "A new SPG4 mutation in a variant form of spastic paraplegia with
RT congenital arachnoid cysts.";
RL Neurology 62:1875-1878(2004).
RN [50]
RP VARIANTS SPG4 LEU-44 AND LEU-361.
RX PubMed=15326248;
RA Chinnery P.F., Keers S.M., Holden M.J., Ramesh V., Dalton A.;
RT "Infantile hereditary spastic paraparesis due to codominant mutations
RT in the spastin gene.";
RL Neurology 63:710-712(2004).
RN [51]
RP VARIANTS SPG4 VAL-195; VAL-406; GLY-493; HIS-499; TRP-503 AND CYS-607.
RX PubMed=16682546; DOI=10.1001/archneur.63.5.750;
RA Crippa F., Panzeri C., Martinuzzi A., Arnoldi A., Redaelli F.,
RA Tonelli A., Baschirotto C., Vazza G., Mostacciuolo M.L., Daga A.,
RA Orso G., Profice P., Trabacca A., D'Angelo M.G., Comi G.P.,
RA Galbiati S., Lamperti C., Bonato S., Pandolfo M., Meola G.,
RA Musumeci O., Toscano A., Trevisan C.P., Bresolin N., Bassi M.T.;
RT "Eight novel mutations in SPG4 in a large sample of patients with
RT hereditary spastic paraplegia.";
RL Arch. Neurol. 63:750-755(2006).
RN [52]
RP VARIANT SPG4 LEU-435.
RX PubMed=16684598; DOI=10.1016/j.nmd.2006.03.009;
RA Magariello A., Muglia M., Patitucci A., Mazzei R., Conforti F.L.,
RA Gabriele A.L., Sprovieri T., Ungaro C., Gambardella A., Mancuso M.,
RA Siciliano G., Branca D., Aguglia U., de Angelis M.V., Longo K.,
RA Quattrone A.;
RT "Novel spastin (SPG4) mutations in Italian patients with hereditary
RT spastic paraplegia.";
RL Neuromuscul. Disord. 16:387-390(2006).
RN [53]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-423.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [54]
RP VARIANTS SPG4 THR-364 AND HIS-380, AND VARIANTS LEU-44 AND HIS-579.
RX PubMed=17594340; DOI=10.1111/j.1468-1331.2007.01861.x;
RA Erichsen A.K., Inderhaug E., Mattingsdal M., Eiklid K.,
RA Tallaksen C.M.;
RT "Seven novel mutations and four exon deletions in a collection of
RT Norwegian patients with SPG4 hereditary spastic paraplegia.";
RL Eur. J. Neurol. 14:809-814(2007).
RN [55]
RP VARIANTS LEU-44; ILE-162 AND GLY-229, AND VARIANTS SPG4 PHE-426 AND
RP SER-460.
RX PubMed=20214791; DOI=10.1186/1471-2377-10-17;
RA Braschinsky M., Tamm R., Beetz C., Sachez-Ferrero E., Raukas E.,
RA Luus S.M., Gross-Paju K., Boillot C., Canzian F., Metspalu A.,
RA Haldre S.;
RT "Unique spectrum of SPAST variants in Estonian HSP patients: presence
RT of benign missense changes but lack of exonic rearrangements.";
RL BMC Neurol. 10:17-17(2010).
RN [56]
RP VARIANTS SPG4 THR-287 DEL; LEU-293; ARG-378; HIS-380; PRO-391;
RP 393-LYS--ALA-396 DEL; THR-409; ARG-410; PRO-436; ASN-441; SER-460;
RP ALA-463; PHE-492; GLY-498; ARG-503 INS; GLY-514 AND THR-580, AND
RP VARIANT LEU-328.
RX PubMed=20932283; DOI=10.1186/1471-2377-10-89;
RA Alvarez V., Sanchez-Ferrero E., Beetz C., Diaz M., Alonso B.,
RA Corao A.I., Gamez J., Esteban J., Gonzalo J.F., Pascual-Pascual S.I.,
RA Lopez de Munain A., Moris G., Ribacoba R., Marquez C., Rosell J.,
RA Marin R., Garcia-Barcina M.J., Del Castillo E., Benito C., Coto E.;
RT "Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in
RT Spanish patients with hereditary spastic paraplegia.";
RL BMC Neurol. 10:89-89(2010).
RN [57]
RP VARIANT SPG4 SER-460, AND VARIANTS LEU-44; ILE-162; LYS-356; SER-365;
RP ARG-382; ILE-407; PHE-422; ASN-445; LEU-482; GLU-512 DEL; VAL-534 AND
RP PRO-562.
RX PubMed=20562464; DOI=10.1136/jnnp.2009.201103;
RA de Bot S.T., van den Elzen R.T., Mensenkamp A.R., Schelhaas H.J.,
RA Willemsen M.A., Knoers N.V., Kremer H.P., van de Warrenburg B.P.,
RA Scheffer H.;
RT "Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch
RT patients: new clinical aspects and 27 novel mutations.";
RL J. Neurol. Neurosurg. Psych. 81:1073-1078(2010).
RN [58]
RP VARIANTS THR-97; ASP-201; SER-314; VAL-360; ALA-464 AND ILE-550, AND
RP VARIANT SPG4 GLY-498.
RX PubMed=20718791; DOI=10.1111/j.1399-0004.2010.01501.x;
RA McCorquodale D.S. III, Ozomaro U., Huang J., Montenegro G.,
RA Kushman A., Citrigno L., Price J., Speziani F., Pericak-Vance M.A.,
RA Zuchner S.;
RT "Mutation screening of spastin, atlastin, and REEP1 in hereditary
RT spastic paraplegia.";
RL Clin. Genet. 79:523-530(2011).
RN [59]
RP VARIANTS SPG4 LEU-413 AND LYS-454.
RX PubMed=20550563; DOI=10.1111/j.1468-1331.2010.03102.x;
RA Battini R., Fogli A., Borghetti D., Michelucci A., Perazza S.,
RA Baldinotti F., Conidi M.E., Ferreri M.I., Simi P., Cioni G.;
RT "Clinical and genetic findings in a series of Italian children with
RT pure hereditary spastic paraplegia.";
RL Eur. J. Neurol. 18:150-157(2011).
CC -!- FUNCTION: ATP-dependent microtubule severing protein. Microtubule
CC severing may promote reorganization of cellular microtubule arrays
CC and the release of microtubules from the centrosome following
CC nucleation. Required for membrane traffic from the endoplasmic
CC reticulum (ER) to the Golgi and for completion of the abscission
CC stage of cytokinesis. May also play a role in axon growth and the
CC formation of axonal branches.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O = ADP + phosphate.
CC -!- ENZYME REGULATION: Allosteric enzyme with a cooperative mechanism;
CC at least two neighbor subunits influence each other strongly in
CC spastin hexamers. Microtubule binding promotes cooperative
CC interactions among spastin subunits.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.45 mM for ATP;
CC Vmax=1.2 nmol/min/ug enzyme;
CC Note=Kinetic parameters shown are for full length enzyme. N-
CC terminally truncated spastin (residues 228-616), which has been
CC shown to exhibit full severing activity, shows a basal ATP
CC turnover rate of 0.78 sec(-1) in the absence of microtubules, a
CC KM of 0.16 mM for ATP, and the ATP turnover rate is extrapolated
CC to 3.83 sec(-1) in the presence of microtubules. ATPase activity
CC shows non-Michaelis-Menten kinetics in the presence of
CC microtubules, but is close to non-cooperative behavior in their
CC absence (PubMed:22637577);
CC -!- SUBUNIT: Homohexamer. Mostly monomeric, but assembles into
CC hexameric structure for short periods of time. Oligomerization
CC seems to be a prerequisite for catalytic activity. Binding to ATP
CC in a cleft between two adjacent subunits stabilizes the
CC homohexameric form. Binds to microtubules at least in part via the
CC alpha-tubulin and beta-tubulin tails. The hexamer adopts a ring
CC conformation through which microtubules pass prior to being
CC severed. Does not interact strongly with tubulin heterodimers.
CC Interacts (via MIT domain) with CHMP1B; the interaction is direct.
CC Interacts with ATL1, RTN1, SSNA1 and ZFYVE27. Isoform 1 but not
CC isoform 3 interacts with RTN2. Interacts with REEP1.
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass membrane protein
CC (Potential). Cytoplasm, cytoskeleton, microtubule organizing
CC center, centrosome. Cytoplasm, cytoskeleton. Cytoplasm,
CC perinuclear region. Endoplasmic reticulum. Endosome. Nucleus.
CC Cytoplasm, cytoskeleton, spindle. Note=Localization to the
CC centrosome is independent of microtubules. Localizes to the
CC midbody of dividing cells, and this requires CHMP1B. Enriched in
CC the distal axons and branches of postmitotic neurons. Isoform 3 is
CC the main endosomal form.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing, Alternative initiation; Named isoforms=4;
CC Comment=Alternative promoter usage of a cryptic promoter in exon
CC 1 can direct the synthesis of N-terminally truncated isoforms,
CC which may also arise from alternative initiation;
CC Name=1; Synonyms=Long, Long variant 1;
CC IsoId=Q9UBP0-1; Sequence=Displayed;
CC Name=2; Synonyms=Long variant 2;
CC IsoId=Q9UBP0-2; Sequence=VSP_000024;
CC Name=3; Synonyms=Short, Short variant 1;
CC IsoId=Q9UBP0-3; Sequence=VSP_036650;
CC Note=Produced by alternative promoter usage. May also be
CC produced by alternative initiation at Met-87 of isoform 1. Major
CC isoform;
CC Name=4; Synonyms=Short variant 2;
CC IsoId=Q9UBP0-4; Sequence=VSP_036650, VSP_000024;
CC Note=Produced by alternative promoter usage and alternative
CC splicing. May also be produced by alternative initiation at
CC Met-87 of isoform 2;
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, kidney, liver,
CC lung, pancreas, placenta and skeletal muscle. The short isoforms
CC may predominate in brain and spinal cord.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal brain, heart, kidney,
CC liver, lung, skeletal muscle, spleen and thymus.
CC -!- DISEASE: Spastic paraplegia 4, autosomal dominant (SPG4)
CC [MIM:182601]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness
CC and spasticity of the lower limbs. Rate of progression and the
CC severity of symptoms are quite variable. Initial symptoms may
CC include difficulty with balance, weakness and stiffness in the
CC legs, muscle spasms, and dragging the toes when walking. In some
CC forms of the disorder, bladder symptoms (such as incontinence) may
CC appear, or the weakness and stiffness may spread to other parts of
CC the body. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the AAA ATPase family. Spastin subfamily.
CC -!- SIMILARITY: Contains 1 MIT domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SPAST";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The making of crooked -
CC Issue 104 of April 2009;
CC URL="http://web.expasy.org/spotlight/back_issues/sptlt104.shtml";
CC -----------------------------------------------------------------------
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DR EMBL; AJ246001; CAB60141.1; -; mRNA.
DR EMBL; AJ246003; CAB60208.1; -; Genomic_DNA.
DR EMBL; AB029006; BAA83035.1; -; mRNA.
DR EMBL; CH471053; EAX00462.1; -; Genomic_DNA.
DR EMBL; BC150260; AAI50261.1; -; mRNA.
DR RefSeq; NP_055761.2; NM_014946.3.
DR RefSeq; NP_955468.1; NM_199436.1.
DR UniGene; Hs.468091; -.
DR PDB; 3EAB; X-ray; 2.50 A; A/B/C/D/E/F=112-196.
DR PDB; 3VFD; X-ray; 3.30 A; A=228-616.
DR PDBsum; 3EAB; -.
DR PDBsum; 3VFD; -.
DR ProteinModelPortal; Q9UBP0; -.
DR SMR; Q9UBP0; 112-196, 324-612.
DR IntAct; Q9UBP0; 2.
DR STRING; 9606.ENSP00000320885; -.
DR PhosphoSite; Q9UBP0; -.
DR DMDM; 12230611; -.
DR PaxDb; Q9UBP0; -.
DR PeptideAtlas; Q9UBP0; -.
DR PRIDE; Q9UBP0; -.
DR Ensembl; ENST00000315285; ENSP00000320885; ENSG00000021574.
DR Ensembl; ENST00000345662; ENSP00000340817; ENSG00000021574.
DR GeneID; 6683; -.
DR KEGG; hsa:6683; -.
DR UCSC; uc002roc.3; human.
DR CTD; 6683; -.
DR GeneCards; GC02P032288; -.
DR HGNC; HGNC:11233; SPAST.
DR HPA; HPA017311; -.
DR MIM; 182601; phenotype.
DR MIM; 604277; gene.
DR neXtProt; NX_Q9UBP0; -.
DR Orphanet; 100985; Autosomal dominant spastic paraplegia type 4.
DR PharmGKB; PA36063; -.
DR eggNOG; COG0464; -.
DR HOGENOM; HOG000225146; -.
DR HOVERGEN; HBG108502; -.
DR InParanoid; Q9UBP0; -.
DR KO; K13254; -.
DR OMA; ATHKSTP; -.
DR OrthoDB; EOG7GXPCR; -.
DR PhylomeDB; Q9UBP0; -.
DR ChiTaRS; SPAST; human.
DR EvolutionaryTrace; Q9UBP0; -.
DR GeneWiki; Spastin; -.
DR GenomeRNAi; 6683; -.
DR NextBio; 26047; -.
DR PRO; PR:Q9UBP0; -.
DR ArrayExpress; Q9UBP0; -.
DR Bgee; Q9UBP0; -.
DR CleanEx; HS_SPAST; -.
DR Genevestigator; Q9UBP0; -.
DR GO; GO:0005813; C:centrosome; IEA:UniProtKB-HAMAP.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-HAMAP.
DR GO; GO:0030496; C:midbody; IEA:UniProtKB-HAMAP.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-HAMAP.
DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB.
DR GO; GO:0008568; F:microtubule-severing ATPase activity; IDA:UniProtKB.
DR GO; GO:0007409; P:axonogenesis; IEA:UniProtKB-HAMAP.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0007109; P:cytokinesis, completion of separation; IMP:UniProtKB.
DR GO; GO:0006888; P:ER to Golgi vesicle-mediated transport; IMP:UniProtKB.
DR GO; GO:0001578; P:microtubule bundle formation; IDA:UniProtKB.
DR GO; GO:0051013; P:microtubule severing; IDA:UniProtKB.
DR GO; GO:0031117; P:positive regulation of microtubule depolymerization; IEA:UniProtKB-HAMAP.
DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR HAMAP; MF_03021; Spastin; 1; -.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR003959; ATPase_AAA_core.
DR InterPro; IPR003960; ATPase_AAA_CS.
DR InterPro; IPR007330; MIT.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR017179; Spastin.
DR PANTHER; PTHR23074:SF15; PTHR23074:SF15; 1.
DR Pfam; PF00004; AAA; 1.
DR Pfam; PF04212; MIT; 1.
DR PIRSF; PIRSF037338; Spastin; 1.
DR SMART; SM00382; AAA; 1.
DR SMART; SM00745; MIT; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS00674; AAA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative initiation;
KW Alternative promoter usage; Alternative splicing; ATP-binding;
KW Cell cycle; Cell division; Complete proteome; Cytoplasm; Cytoskeleton;
KW Developmental protein; Differentiation; Endoplasmic reticulum;
KW Endosome; Hereditary spastic paraplegia; Hydrolase; Membrane;
KW Microtubule; Neurodegeneration; Neurogenesis; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 616 Spastin.
FT /FTId=PRO_0000084763.
FT TRANSMEM 57 77 Helical; (Potential).
FT DOMAIN 120 195 MIT.
FT NP_BIND 382 389 ATP (Probable).
FT REGION 1 300 Required for interaction with RTN1.
FT REGION 1 194 Required for midbody localization.
FT REGION 1 80 Required for interaction with ATL1.
FT REGION 1 50 Required for nuclear localization.
FT REGION 50 87 Required for interaction with SSNA1 and
FT microtubules.
FT REGION 112 196 Sufficient for interaction with CHMP1B.
FT REGION 114 200 Required for interaction with
FT microtubules.
FT REGION 226 328 Sufficient for interaction with
FT microtubules (By similarity).
FT REGION 228 616 Sufficient for microtubule severing.
FT REGION 270 328 Required for interaction with
FT microtubules and microtubule severing.
FT REGION 310 312 Required for interaction with
FT microtubules.
FT MOTIF 4 11 Nuclear localization signal.
FT MOTIF 59 67 Nuclear export signal.
FT MOTIF 309 312 Nuclear localization signal.
FT MOD_RES 245 245 Phosphoserine.
FT MOD_RES 268 268 Phosphoserine.
FT MOD_RES 306 306 Phosphothreonine.
FT VAR_SEQ 1 86 Missing (in isoform 3 and isoform 4).
FT /FTId=VSP_036650.
FT VAR_SEQ 197 228 Missing (in isoform 2 and isoform 4).
FT /FTId=VSP_000024.
FT VARIANT 44 44 S -> L (rare polymorphism which modifies
FT the phenotype of SPG4 disease; may
FT decrease the activity of the alternative
FT promoter which directs the synthesis of
FT isoform 3 and isoform 4;
FT dbSNP:rs121908515).
FT /FTId=VAR_010194.
FT VARIANT 45 45 P -> Q (rare polymorphism which modifies
FT the phenotype of SPG4 disease).
FT /FTId=VAR_027205.
FT VARIANT 97 97 P -> T (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067628.
FT VARIANT 162 162 V -> I (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance; dbSNP:rs141944844).
FT /FTId=VAR_067563.
FT VARIANT 195 195 L -> V (in SPG4).
FT /FTId=VAR_026758.
FT VARIANT 201 201 V -> D (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067629.
FT VARIANT 229 229 S -> G.
FT /FTId=VAR_067630.
FT VARIANT 287 287 Missing (in SPG4).
FT /FTId=VAR_067631.
FT VARIANT 293 293 P -> L (in SPG4).
FT /FTId=VAR_067632.
FT VARIANT 314 314 L -> S (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067633.
FT VARIANT 328 328 I -> L (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067634.
FT VARIANT 344 344 I -> K (in SPG4; abrogates ATPase
FT activity and promotes microtubule
FT binding).
FT /FTId=VAR_019448.
FT VARIANT 347 347 Q -> K (in SPG4; promotes microtubule
FT binding).
FT /FTId=VAR_027206.
FT VARIANT 356 356 E -> K (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067564.
FT VARIANT 360 360 L -> V (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067635.
FT VARIANT 361 361 P -> L (in SPG4).
FT /FTId=VAR_027207.
FT VARIANT 362 362 S -> C (in SPG4).
FT /FTId=VAR_010195.
FT VARIANT 364 364 R -> T (in SPG4).
FT /FTId=VAR_067636.
FT VARIANT 365 365 P -> S (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067565.
FT VARIANT 370 370 G -> R (in SPG4; promotes microtubule
FT binding and the formation of thick
FT microtubule bundles).
FT /FTId=VAR_027208.
FT VARIANT 378 378 L -> Q (in SPG4).
FT /FTId=VAR_019439.
FT VARIANT 378 378 L -> R (in SPG4).
FT /FTId=VAR_067637.
FT VARIANT 380 380 L -> H (in SPG4).
FT /FTId=VAR_067638.
FT VARIANT 381 381 F -> C (in SPG4; promotes microtubule
FT binding and the formation of thick
FT microtubule bundles).
FT /FTId=VAR_027209.
FT VARIANT 382 382 G -> R (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067566.
FT VARIANT 386 386 N -> K (in SPG4; abrogates ATPase
FT activity, promotes microtubule binding
FT and the formation of thick microtubule
FT bundles).
FT /FTId=VAR_027210.
FT VARIANT 386 386 N -> S (in SPG4).
FT /FTId=VAR_019440.
FT VARIANT 388 388 K -> R (in SPG4; abrogates ATPase
FT activity, promotes microtubule binding
FT and the formation of thick microtubule
FT bundles and impairs traffic from the ER
FT to Golgi).
FT /FTId=VAR_027211.
FT VARIANT 390 390 M -> V (in SPG4).
FT /FTId=VAR_019441.
FT VARIANT 391 391 L -> P (in SPG4).
FT /FTId=VAR_067639.
FT VARIANT 393 396 Missing (in SPG4).
FT /FTId=VAR_067640.
FT VARIANT 399 399 S -> L (in SPG4).
FT /FTId=VAR_027212.
FT VARIANT 404 404 Missing (in SPG4).
FT /FTId=VAR_019449.
FT VARIANT 406 406 I -> V (in SPG4).
FT /FTId=VAR_026759.
FT VARIANT 407 407 S -> I (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067567.
FT VARIANT 407 407 S -> R (in SPG4).
FT /FTId=VAR_019450.
FT VARIANT 409 409 A -> T (in SPG4).
FT /FTId=VAR_067641.
FT VARIANT 410 410 S -> R (in SPG4).
FT /FTId=VAR_067642.
FT VARIANT 413 413 S -> L (in SPG4).
FT /FTId=VAR_067568.
FT VARIANT 422 422 L -> F (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067569.
FT VARIANT 423 423 V -> L (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035902.
FT VARIANT 424 424 R -> G (in SPG4).
FT /FTId=VAR_010196.
FT VARIANT 426 426 L -> F (in SPG4).
FT /FTId=VAR_067643.
FT VARIANT 426 426 L -> V (in SPG4; promotes microtubule
FT binding and the formation of thick
FT microtubule bundles).
FT /FTId=VAR_027213.
FT VARIANT 435 435 P -> L (in SPG4).
FT /FTId=VAR_027214.
FT VARIANT 436 436 S -> F (in SPG4).
FT /FTId=VAR_027215.
FT VARIANT 436 436 S -> P (in SPG4).
FT /FTId=VAR_067644.
FT VARIANT 441 441 D -> G (in SPG4).
FT /FTId=VAR_027216.
FT VARIANT 441 441 D -> N (in SPG4).
FT /FTId=VAR_067645.
FT VARIANT 445 445 S -> N (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067570.
FT VARIANT 448 448 C -> Y (in SPG4; abrogates binding to the
FT tail of beta-3-tubulin, abolishes
FT microtubule severing and promotes the
FT formation of thick microtubule bundles).
FT /FTId=VAR_010197.
FT VARIANT 454 454 E -> K (in SPG4).
FT /FTId=VAR_067571.
FT VARIANT 459 459 R -> G (in SPG4).
FT /FTId=VAR_027217.
FT VARIANT 460 460 R -> C (in SPG4; promotes microtubule
FT binding and the formation of thick
FT microtubule bundles).
FT /FTId=VAR_027218.
FT VARIANT 460 460 R -> L (in SPG4).
FT /FTId=VAR_027219.
FT VARIANT 460 460 R -> S (in SPG4).
FT /FTId=VAR_067572.
FT VARIANT 463 463 T -> A (in SPG4).
FT /FTId=VAR_067646.
FT VARIANT 464 464 E -> A (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067647.
FT VARIANT 470 470 D -> V (in SPG4; dbSNP:rs28939368).
FT /FTId=VAR_027220.
FT VARIANT 482 482 V -> L (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067573.
FT VARIANT 485 485 A -> V (in SPG4).
FT /FTId=VAR_027221.
FT VARIANT 489 489 P -> L (in SPG4).
FT /FTId=VAR_027222.
FT VARIANT 492 492 L -> F (in SPG4).
FT /FTId=VAR_067648.
FT VARIANT 493 493 D -> G (in SPG4).
FT /FTId=VAR_026760.
FT VARIANT 498 498 R -> G (in SPG4).
FT /FTId=VAR_067649.
FT VARIANT 499 499 R -> C (in SPG4; abrogates ATPase
FT activity, promotes microtubule binding
FT and the formation of thick microtubule
FT bundles).
FT /FTId=VAR_010198.
FT VARIANT 499 499 R -> H (in SPG4).
FT /FTId=VAR_026761.
FT VARIANT 503 503 R -> L (in SPG4).
FT /FTId=VAR_019442.
FT VARIANT 503 503 R -> RR (in SPG4).
FT /FTId=VAR_067650.
FT VARIANT 503 503 R -> W (in SPG4).
FT /FTId=VAR_026762.
FT VARIANT 512 512 E -> D (in SPG4).
FT /FTId=VAR_027223.
FT VARIANT 512 512 Missing (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067574.
FT VARIANT 514 514 R -> G (in SPG4).
FT /FTId=VAR_067651.
FT VARIANT 515 515 Missing (in SPG4).
FT /FTId=VAR_019443.
FT VARIANT 534 534 L -> P (in SPG4).
FT /FTId=VAR_019444.
FT VARIANT 534 534 L -> V (found at homozygosity in two
FT children with hereditary spastic
FT paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067575.
FT VARIANT 550 550 T -> I (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067652.
FT VARIANT 551 551 A -> Y (in SPG4; requires 2 nucleotide
FT substitutions).
FT /FTId=VAR_019451.
FT VARIANT 555 555 D -> N (in SPG4).
FT /FTId=VAR_027224.
FT VARIANT 556 556 A -> V (in SPG4; promotes microtubule
FT binding and the formation of thick
FT microtubule bundles).
FT /FTId=VAR_027225.
FT VARIANT 559 559 G -> D (in SPG4).
FT /FTId=VAR_027226.
FT VARIANT 562 562 R -> G (in SPG4).
FT /FTId=VAR_027227.
FT VARIANT 562 562 R -> P (in a patient with hereditary
FT spastic paraplegia; unknown pathological
FT significance).
FT /FTId=VAR_067576.
FT VARIANT 562 562 R -> Q (in SPG4).
FT /FTId=VAR_027228.
FT VARIANT 579 579 N -> H (found in patients with hereditary
FT spastic paraplegia; unknown pathological
FT significance; dbSNP:rs144594804).
FT /FTId=VAR_067653.
FT VARIANT 580 580 I -> T (in SPG4).
FT /FTId=VAR_067654.
FT VARIANT 584 584 D -> H (in SPG4).
FT /FTId=VAR_010199.
FT VARIANT 607 607 W -> C (in SPG4).
FT /FTId=VAR_026763.
FT VARIANT 614 614 T -> I (in SPG4; variant form with
FT congenital arachnoid cysts).
FT /FTId=VAR_019445.
FT VARIANT 615 615 T -> I (in SPG4).
FT /FTId=VAR_019452.
FT MUTAGEN 1 1 M->V: Cytoplasmic and nuclear.
FT MUTAGEN 87 87 M->V: Exclusively cytoplasmic.
FT MUTAGEN 120 120 H->D: Impairs binding to CHMP1B. Impairs
FT midbody localization; when associated
FT with D-124.
FT MUTAGEN 124 124 F->A: Impairs binding to CHMP1B.
FT MUTAGEN 124 124 F->D: Impairs binding to CHMP1B. Impairs
FT midbody localization; when associated
FT with D-120.
FT MUTAGEN 310 312 KKK->QQQ: Loss of microtubule-binding.
FT MUTAGEN 388 388 K->A: Abrogates ATPase activity and
FT abolishes microtubule severing.
FT MUTAGEN 415 415 Y->A: Abrogates binding to the tail of
FT alpha-tubulin and beta-3-tubulin, impairs
FT ATPase activity and abolishes microtubule
FT severing.
FT MUTAGEN 442 442 E->Q: Abrogates ATP hydrolysis, abolishes
FT microtubule severing, stabilizes the
FT homohexameric form, and promotes
FT microtubule binding and redistribution
FT from the endosome to microtubules.
FT MUTAGEN 451 451 R->G: Abrogates binding to the tail of
FT alpha-tubulin and beta-3-tubulin, impairs
FT ATPase activity and abolishes microtubule
FT severing.
FT MUTAGEN 457 457 A->E: Abrogates binding to the tail of
FT alpha-tubulin and beta-3-tubulin and
FT abolishes microtubule severing.
FT HELIX 112 136
FT STRAND 139 141
FT HELIX 142 144
FT HELIX 146 161
FT HELIX 169 195
FT HELIX 328 330
FT HELIX 341 343
FT HELIX 348 357
FT HELIX 359 363
FT TURN 365 367
FT HELIX 370 372
FT STRAND 376 383
FT HELIX 388 398
FT STRAND 402 406
FT HELIX 420 432
FT STRAND 433 441
FT HELIX 443 446
FT HELIX 458 472
FT STRAND 480 487
FT HELIX 489 491
FT HELIX 494 497
FT STRAND 502 505
FT HELIX 511 522
FT HELIX 531 540
FT TURN 541 543
FT HELIX 546 556
FT HELIX 559 562
FT STRAND 573 575
FT HELIX 582 591
FT HELIX 598 610
SQ SEQUENCE 616 AA; 67197 MW; 75E5FC5787132B4C CRC64;
MNSPGGRGKK KGSGGASNPV PPRPPPPCLA PAPPAAGPAP PPESPHKRNL YYFSYPLFVG
FALLRLVAFH LGLLFVWLCQ RFSRALMAAK RSSGAAPAPA SASAPAPVPG GEAERVRVFH
KQAFEYISIA LRIDEDEKAG QKEQAVEWYK KGIEELEKGI AVIVTGQGEQ CERARRLQAK
MMTNLVMAKD RLQLLEKMQP VLPFSKSQTD VYNDSTNLAC RNGHLQSESG AVPKRKDPLT
HTSNSLPRSK TVMKTGSAGL SGHHRAPSYS GLSMVSGVKQ GSGPAPTTHK GTPKTNRTNK
PSTPTTATRK KKDLKNFRNV DSNLANLIMN EIVDNGTAVK FDDIAGQDLA KQALQEIVIL
PSLRPELFTG LRAPARGLLL FGPPGNGKTM LAKAVAAESN ATFFNISAAS LTSKYVGEGE
KLVRALFAVA RELQPSIIFI DEVDSLLCER REGEHDASRR LKTEFLIEFD GVQSAGDDRV
LVMGATNRPQ ELDEAVLRRF IKRVYVSLPN EETRLLLLKN LLCKQGSPLT QKELAQLARM
TDGYSGSDLT ALAKDAALGP IRELKPEQVK NMSASEMRNI RLSDFTESLK KIKRSVSPQT
LEAYIRWNKD FGDTTV
//

MIM 182601
*RECORD*
*FIELD* NO
182601
*FIELD* TI
#182601 SPASTIC PARAPLEGIA 4, AUTOSOMAL DOMINANT; SPG4
;;FAMILIAL SPASTIC PARAPLEGIA, AUTOSOMAL DOMINANT, 2; FSP2
read more*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
spastic paraplegia-4 (SPG4) is caused by heterozygous mutation in the
SPAST gene (604277) on chromosome 2p22.

DESCRIPTION

The hereditary spastic paraplegias (SPG, HSP) are a group of clinically
and genetically diverse inherited disorders characterized predominantly
by progressive lower extremity spasticity and weakness. SPG is
classified by mode of inheritance (autosomal dominant, autosomal
recessive, and X-linked) and whether the primary symptoms occur in
isolation ('uncomplicated') or with other neurologic abnormalities
('complicated').

Pure SPG4 is the most common form of autosomal dominant hereditary SPG,
comprising up to 45% of cases (Svenson et al., 2001; Crippa et al.,
2006).

For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal dominant spastic paraplegia, see SPG3A
(182600).

CLINICAL FEATURES

In 5 of 7 French families and in 1 large Dutch pedigree with a form of
autosomal dominant familial spastic paraplegia, Hazan et al. (1994)
found linkage to a locus, which they termed FSP2 (also known as SPG4),
on chromosome 2p. This finding distinguished the disease from autosomal
dominant spastic paraplegia-3 (182600), which had been mapped to
chromosome 14. Age of onset in the 6 families showing linkage to 2p
varied widely within families and the mean age at onset ranged from 20
to 39 years. Thus, age of onset may be a poor criterion for classifying
autosomal dominant spastic paraplegia. Anticipation in the age of onset
was observed in 2 of the kindreds.

Durr et al. (1996) reported 12 families with autosomal dominant spastic
paraplegia linked to the SPG4 locus on chromosome 2. Age of onset ranged
from infancy to 63 years. The clinical expression of the disorder within
a family included asymptomatic patients who were unaware of their
condition, mildly affected individuals who had spastic gait but were
able to walk independently, and severely affected patients who were
wheelchair bound. Durr et al. (1996) commented on the extensive intra-
and interfamilial clinical variation.

Nielsen et al. (1998) evaluated 5 families with 2p-linked pure spastic
paraplegia. In 2 families, nonprogressive 'congenital' spastic
paraplegia was seen in some affected members, whereas adult-onset
progressive spastic paraplegia was present in others. Low backache was
reported as a late symptom by 47% of the 63 at-risk members in the 5
families. Brain and total spinal cord MRI disclosed no significant
abnormalities. Nielsen et al. (1998) concluded that SPG4 is a
phenotypically heterogeneous disorder, characterized by both
interfamilial and intrafamilial variation.

Nance et al. (1998) found striking variation in clinical features in 4
families with spastic paraplegia with linkage to chromosome 2 markers.
Only mild neurologic signs were observed in some subjects. The clinical
features of 1 family had previously been described by Boustany et al.
(1987). Onset was generally in the third to fifth decades with an
average onset age of 35 years (range, 5 to 61 years). All clearly
affected patients had scissoring gait, and in all who were examined at
least 2 of the following were found: extensor plantar responses,
increased knee and ankle reflexes, increased tone, muscle spasms, or leg
cramps. Urinary urgency or other symptoms compatible with a neurogenic
bladder, leg weakness, and decreased vibration sense were present in
some but not all patients.

Byrne et al. (1997, 1998) presented a family with autosomal dominant
hereditary spastic paraplegia and a specific form of cognitive
impairment who showed linkage to the SPG4 locus on chromosome 2. The
pattern of cognitive impairment in this family was characterized
primarily by deficits in visual-spatial functions. Dysfunction
manifested itself by difficulty in carrying out new tasks,
forgetfulness, poor spatial perception, and impaired visual-motor
coordination. By haplotype analysis the presence of the mutant gene was
identified in an individual who, at the age of 57, had the same pattern
of cognitive impairment but no spastic paraplegia. Furthermore, 6
individuals who presented with the disease haplotype had normal
neurologic and neuropsychologic examinations. All 6 were below the
maximal age of onset in the family, namely, 60 years. In this Irish
family the cognitive impairment was considered to be a manifestation of
the SPG4 gene mutation.

Reid et al. (1999) investigated 35 individuals from 4 families of Welsh
origin, 22 of whom had 'pure' hereditary spastic paraplegia, for the
presence of subclinical cognitive impairment. They found significant
reductions in scores on the Mini-Mental State Examination (MMSE) among
affected individuals compared to controls. To assess whether the lower
MMSE scores were restricted to subjects older than 50 years, scores for
affected subjects 50 years of age or younger were compared to those of
controls. A significant difference in score remained. One of the
families was linked to the chromosome 2 locus, while 2 others showed
linkage to none of the loci known at that time. There was no significant
difference between the results of these 2 groups.

McMonagle et al. (2000) compared the phenotypic expressions of autosomal
dominant hereditary spastic paresis in several families with a mutation
in the SPG4 gene and several families without a mutation in SPG4. In the
mutation-positive group, age of onset was later, disability score was
greater, progression of disease was faster, wheelchair use was greater
(40.9% vs 4.8% in the mutation-excluded group), there was greater
abnormal vibration sensation in the lower limbs (68.2% vs 19%), and
fewer individuals were asymptomatic (18.2% vs 42.9%). Dementia was more
prevalent in the mutation-positive group. McMonagle et al. (2000)
emphasized the finding of cognitive impairment as a feature of SPG4
mutations.

White et al. (2000) reported a patient with familial SPG4 who had
clinical dementia. Postmortem neuropathologic examination showed
neuronal loss and tau- (MAPT; 157140) immunoreactive neurofibrillary
tangles in the hippocampus and tau-immunoreactive balloon cells in the
limbic area and neocortex. Lewy bodies were present in the substantia
nigra. White et al. (2000) suggested that these findings confirmed an
association of dementia with SPG4.

McMonagle et al. (2004) used several measures of cognitive function to
assess 11 patients from 3 families in whom SPG4 was confirmed by genetic
analysis or linkage. SPG4 patients scored significantly lower on the
Cambridge cognitive examination (CAMCOG) (mean score of 73.5 compared to
91.7 in controls). After approximately 3 years, the patients' mean score
fell to 64.4, whereas the mean control score declined slightly to 90.8.
Deficits in the SPG4 patients were noted in attention, language
expression, memory, and abstraction. Behavior assessment found that SPG4
patients exhibited agitation, aggression, apathy, irritability,
depression, and disinhibition. Accounting for age, McMonagle et al.
(2004) concluded that subtle changes in cognitive function in patients
with SPG4 may begin after age 40 years, with more severe decline after
age 60.

Orlacchio et al. (2004) reported 32 patients from 9 families from
southern Scotland with SPG4. Age at onset varied from 11 to 53 years. In
addition to classic features of hereditary spastic paraplegia, 2 of the
32 patients had mental retardation and 2 other patients had a thin
corpus callosum and cerebellar atrophy. All affected members had the
same mutation in the SPG4 gene (604277.0014), and haplotype analysis
suggested a founder effect.

Orlacchio et al. (2004) reported a large Italian family in which all 16
members who had SPG4 also had congenital arachnoid cysts at the
cerebellopontine angle ranging in size from 21 to 31 mm. Six patients
also had mental retardation. Genetic analysis confirmed a mutation in
the SPG4 gene.

McDermott et al. (2006) reported a patient with SPG4 who developed
walking difficulties in his late teens with deteriorating gait in his
20s; he was wheelchair-dependent at age 35. He later developed stiffness
in the upper limbs, bladder dysfunction, dysarthria, and swallowing
difficulties. In his 40s, he developed respiratory insufficiency and
distal muscle wasting in the lower limbs. Molecular analysis identified
a mutation in the SPG4 gene (S445R; 604277.0021). The findings of bulbar
and respiratory involvement, as well as lower motor neuron degeneration,
broadened the phenotype associated with mutations in the SPG4 gene.

Orlacchio et al. (2008) reported a large 4-generation Italian family
with SPG4 confirmed by genetic analysis. The mean ages at onset were
17.5 and 18.8 years for symptoms of the lower and upper limbs,
respectively. There was a general impression of genetic anticipation
spanning the 4 generations. All affected individuals had spasticity of
the lower limbs and pyramidal tract signs such as hyperreflexia,
extensor plantar responses, or both, and pes cavus. All patients also
had weak intrinsic hand muscles, with severe amyotrophy most relevant in
the thenar eminence. Peroneal muscle wasting was reported in five
patients, and many used a cane. Other associated features included
impaired vibration sensation and cognitive dysfunctions. All patients
except 1 had temporal lobe epilepsy with partial complex seizures
associated with hippocampal sclerosis.

Murphy et al. (2009) reported a family in which 12 members had SPG4 due
to a deletion of exon 17 in the SPG4 gene (Beetz et al., 2007).
Cognitive assessment performed over a 7-year period found that all 4
patients who were older than 60 years developed mild to moderate
cognitive decline. Two younger patients aged 48 and 40, respectively,
had mild cognitive impairment. Genetic analysis of this family was
unusual because 4 patients with the SPG4 deletion also carried a
microdeletion in the NIPA1 gene (608145), which causes SPG6 (600363);
only 2 of these 4 had cognitive impairment. Five patients with only the
SPG4 deletion had cognitive impairment, including 2 who did not have
clinical signs of SPG. Another family member with only the NIPA1
microdeletion lacked clinical signs of SPG or cognitive impairment at
age 57. Murphy et al. (2009) concluded that SPG4 is associated with
cognitive decline, and that the SPG6 microdeletion does not have a
clinical phenotype in this family. Postmortem examination of the
proband, who had both deletions as well as SPG and cognitive impairment,
showed a markedly atrophic spinal cord with degeneration of the
corticospinal tracts, and superficial spongiosis and widespread
ubiquitin-positive inclusions in the neocortex and white matter.

MAPPING

In 5 French families and 1 large Dutch pedigree with autosomal dominant
spastic paraplegia, Hazan et al. (1994) found linkage markers in the
2p24-p21 region. An analysis of recombination events and multipoint
linkage placed this form of the disease within a 4-cM interval flanked
by loci D2S400 and D2S367. In 4 Caucasian North American families and in
1 family from Tunisia, Hentati et al. (1994) found linkage of late-onset
SPG to DNA markers on chromosome 2p in 4 of the families. Pathologic
findings in a member of one of the chromosome 2-linked families had
previously been reported by Sack et al. (1978).

Scott et al. (1997) examined 11 Caucasian pedigrees with autosomal
dominant 'uncomplicated' familial spastic paraplegia for linkage to the
previously identified loci on 2p, 14q (SPG3A), and 15q (SPG6; 600363).
Chromosome 15q was excluded for all families. Five families showed
evidence for linkage to 2p, 1 family to 14q, and 5 families remained
indeterminate. Recombination events reduced the 2p minimum candidate
region to a 3-cM interval between D2S352 and D2S367, and supported the
previously reported 7-cM minimum candidate region for 14q. Age of onset
was highly variable, indicating that subtypes of SPG are more
appropriately defined on a genetic basis than by age of onset.
Comparison of age of onset in parent-child pairs was suggestive of
anticipation, with a median difference of 9.0 years (p less than
0.0001).

MOLECULAR GENETICS

Using the repeat expansion detection (RED) method, Nielsen et al. (1997)
analyzed 21 affected individuals from 6 SPG4 Danish families with SPG
linked to 2p24-p21. They found that 20 of 21 affected individuals showed
CAG repeat expansions of the SPG4 gene (604277.0006) versus 2 of 21
healthy spouses, demonstrating a strongly statistically significant
association between the occurrence of the repeat expansion and the
disease. Presumably, CAG repeat expansion is involved as a dynamic
mutation in SPG4. They estimated the expansion to be equal to or greater
than 60 CAG repeat copies in the affected individuals.

Benson et al. (1998) analyzed 20 familial spastic paraplegia families,
including 4 for which there was evidence for linkage to the SPG4 region
on 2p24-p21, and found that in most cases the repeat expansion detected
by the RED method was due to nonpathogenic expansions of the chromosome
18q21.1 SEF2-1 locus (TCF4; 602272) or the 17q21.3 ERDA1 locus (603279).
Polymorphic expansions at SEF2-1 and ERDA1 appeared frequent and can
confound RED studies in the search for genes causing disorders
demonstrating anticipation. In 6 SPG families, however, the CAG repeat
expansion was detected in a subset of affected and at-risk individuals
that did not result from expansion of either of these loci. Overall, 11
of 37 (30%) of the SPG patients with a CAG/CTG repeat expansion were
unaccounted for by the SEF2-1 and ERDA1 loci, compared with 2 of 23 (9%)
of the unaffected at-risk individuals and none of 19 controls. In the
majority of cases the novel expansions were shorter than those
previously reported.

Fonknechten et al. (2000) analyzed DNA from 87 unrelated patients with
autosomal dominant hereditary spastic paraplegia and detected 34 novel
mutations scattered along the coding region of the SPG4 gene. They found
missense (28%), nonsense (15%), and splice site point (26.5%) mutations
as well as deletions (23%) and insertions (7.5%). Mean age at onset was
29 +/- 17 years, with a range of 0 to 74 years. Disease severity was
highly variable among patients, and disease progression was actually
faster in the late-onset group. Penetrance was age-dependent and
incomplete even in older mutation carriers (85% after 40 years). Six
percent of 238 mutation carriers were asymptomatic, while 20% of
carriers were unaware of their symptoms. There was no difference in
either age of onset or clinical severity among groups of patients with
missense mutations versus truncation mutations.

Svenson et al. (2001) stated that pure hereditary spastic paraplegia
type 4 is the most common form of autosomal dominant hereditary SPG.
They screened the spastin gene (604277) for mutations in 15 families
showing linkage to the SPG4 locus and identified 11 mutations, 10 of
which were novel. In 15 of 76 unrelated individuals with hereditary
spastic paraplegia, Meijer et al. (2002) identified 5 previously
reported mutations and 8 novel mutations in the SPG4 gene.

Svenson et al. (2004) identified 2 rare polymorphisms in the SPG4 gene:
ser44 to leu (S44L; 604277.0015) and pro45 to gln (P45Q; 604277.0017).
In affected members of 4 SPG4 families, the presence of either the S44L
or P45Q polymorphism in addition to a disease-causing SPG4 mutation
(see, e.g., 604277.0016; 604277.0018) resulted in an earlier age at
disease onset. Svenson et al. (2004) concluded that the S44L and P45Q
polymorphisms, though benign alone, modified the SPG4 phenotype when
present with another SPG4 mutation.

Depienne et al. (2006) identified 19 different mutations in the SPG4
gene in 18 (12%) of 146 unrelated mostly European patients with
progressive spastic paraplegia. Most of the patients had no family
history of the disorder.

In 13 (26%) of 50 unrelated Italian patients with pure hereditary
spastic paraplegia (HSP), Crippa et al. (2006) identified 12 different
mutations in the SPG4 gene, including 8 novel mutations. All 5 of the
familial cases analyzed carried an SPG4 mutation, confirming that the
most common form of autosomal dominant HSP is caused by mutations in
this gene. Eight (18%) of 45 sporadic patients had a SPG4 mutation. No
mutations were identified in 10 additional patients with complicated
HSP. Genotype-phenotype correlations were not observed.

In 24 (20%) of 121 probands with autosomal dominant SPG in whom
mutations in the SPG4 gene were not detected by DHPLC, Depienne et al.
(2007) identified 16 different heterozygous exonic deletions in the SPG4
gene using multiplex ligation-dependent probe amplification (MLPA). The
deletions ranged in size from 1 exon to the whole coding sequence. The
patients with deletions showed a similar clinical phenotype as those
with point mutations but an earlier age at onset. The findings confirmed
that haploinsufficiency of SPG4 is a major cause of autosomal dominant
SPG and that exonic deletions account for a large proportion of
mutation-negative SPG4 patients, justifying the inclusion of gene dosage
studies in appropriate clinical scenarios. Depienne et al. (2007) stated
that over 150 different pathogenic mutations in the SPG4 gene had been
identified to date.

Using MLPA analysis, Beetz et al. (2007) identified partial deletions of
the SPG4 gene in 7 of 8 families who had been linked to the region, but
in whom mutation screening had not identified mutations. The families
had been previously reported by Lindsey et al. (2000), McMonagle et al.
(2000), Meijer et al. (2002), and Svenson et al. (2001). The findings
indicated that large genomic deletions in SPG4 are not uncommon and
should be part of a workup for autosomal dominant SPG.

Mitne-Neto et al. (2007) identified a heterozygous tandem duplication of
exons 10 through 12 of the SPG4 gene (604277.0022) in affected
individuals of a large Brazilian kindred with spastic paraplegia,
originally reported by Starling et al. (2002). In this family, Starling
et al. (2002) noted that there were 24 affected men and only 1 affected
woman, but X-linked inheritance was ruled out. The authors found strong
linkage to the SPG4 locus, but no mutations were identified in the
coding region of the SPG4 gene. The results of Mitne-Neto et al. (2007)
thus confirmed the diagnosis of SPG4. At the time of the latter report,
12 of 30 mutation carriers had no clinical complaints. Among these
patients, 9 of 14 female carriers had no complaints, indicating
sex-dependent penetrance in this family, with women being partially
protected.

Shoukier et al. (2009) identified SPG4 mutations in 57 (28.5%) of 200
unrelated, mostly German patients with SPG. There were 47 distinct
mutations identified, including 29 novel mutations. In a review of other
reported mutations, the authors found that most (72.7%) of the mutations
were clustered in the C-terminal AAA domain of the SPG4 gene. However,
clustering was also observed in the MIT (microtubule interacting and
trafficking), MTBD (microtubule-binding domain), and an N-terminal
region (residues 228 to 269). In the original cohort of 57 patients,
there was a tentative genotype-phenotype correlation indicating that
missense mutations were associated with an earlier onset of the disease.

ANIMAL MODEL

Du et al. (2010) showed that exogenous expression of wildtype Drosophila
or human spastin rescued behavioral and cellular defects in spastin-null
flies equivalently. Flies coexpressing 1 copy of wildtype human spastin
and 1 copy with the K388R catalytic domain mutation in the fly
spastin-null background exhibited aberrant distal synapse morphology and
microtubule distribution, similar to but less severe than spastin nulls.
R388 or a separate nonsense mutation acted dominantly and were
sufficient to confer partial rescue. As in humans, both L44
(604277.0015) and Q45 (604277.0017) were largely silent when
heterozygous, but exacerbated mutant phenotypes when expressed in trans
with R388.

CYTOGENETICS

Miura et al. (2011) reported a 4-generation Japanese family from the
Miyazaki prefecture in southern Japan with autosomal dominant SPG.
RT-PCR and sequencing of affected individuals identified a heterozygous
70-kb deletion of 2p23 encompassing exons 1 to 4 of the SPAST gene as
well as exons 1 to 3 of the neighboring DPY30 (612032) gene, located
approximately 24 kb upstream of SPAST in a head-to-head orientation. The
clinical features included early childhood onset of slowly progressive
spastic paraplegia, decreased vibration sense at the ankles, urinary
disturbances, and mild cognitive impairment. All 4 affected females had
miscarriages, which Miura et al. (2011) speculated may have resulted
from loss of DPY30, which plays a role in the regulation of X chromosome
dosage compensation and possibly affects sex determination in C. elegans
(Hsu and Meyer, 1994).

NOMENCLATURE

Hazan et al. (1993) referred to the form of autosomal dominant spastic
paraplegia encoded by a gene on chromosome 14q as FSP1, and Hazan et al.
(1994) referred to the form encoded by a gene on chromosome 2p as FSP2.
The genes for these 2 disorders are also symbolized SPG3 and SPG4,
respectively.

*FIELD* RF
1. Beetz, C.; Zuchner, S.; Ashley-Koch, A.; Auer-Grumbach, M.; Byrne,
P.; Chinnery, P. F.; Hutchinson, M.; McDermott, C. J.; Meijer, I.
A.; Nygren, A. O. H.; Pericak-Vance, M.; Pyle, A.; Rouleau, G. A.;
Schickel, J.; Shaw, P. J.; Deufel, T.: Linkage to a known gene but
no mutation identified: comprehensive reanalysis of SPG4 HSP pedigrees
reveals large deletions as the sole cause. (Letter) Hum. Mutat. 28:
739-740, 2007.

2. Benson, K. F.; Horwitz, M.; Wolff, J.; Friend, K.; Thompson, E.;
White, S.; Richards, R. I.; Raskind, W. H.; Bird, T. D.: CAG repeat
expansion in autosomal dominant familial spastic paraparesis: novel
expansion in a subset of patients. Hum. Molec. Genet. 7: 1779-1786,
1998.

3. Boustany, R.-M.; Fleischnick, E.; Alper, C. A.; Marazita, M. L.;
Spence, M. A.; Martin, J. B.; Kolodny, E. H.: The autosomal dominant
form of 'pure' familial spastic paraplegia: clinical findings and
linkage analysis of a large pedigree. Neurology 37: 910-915, 1987.

4. Byrne, P.; Webb, S.; Harbourne, G.; MacSweeney, F.; Hutchinson,
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5. Byrne, P. C.; Webb, S.; McSweeney, F.; Burke, T.; Hutchinson, M.;
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1569-1573, 1994.

13. Hazan, J.; Lamy, C.; Melki, J.; Munnich, A.; de Recondo, J.; Weissenbach,
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163-167, 1993.

14. Hentati, A.; Pericak-Vance, M. A.; Lennon, F.; Wasserman, B.;
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T.: Linkage of a locus for autosomal dominant familial spastic paraplegia
to chromosome 2p markers. Hum. Molec. Genet. 3: 1867-1871, 1994.

15. Hsu, D. R.; Meyer, B. J.: The dpy-30 gene encodes an essential
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16. Lindsey, J. C.; Lusher, M. E.; McDermott, C. J.; White, K. D.;
Reid, E.; Rubinsztein, D. C.; Bashir, R.; Hazan, J.; Shaw, P. J.;
Bushby, K. M. D.: Mutation analysis of the spastin gene (SPG4) in
patients with hereditary spastic paraparesis. J. Med. Genet. 37:
759-765, 2000.

17. McDermott, C. J.; Burness, C. E.; Kirby, J.; Cox, L. E.; Rao,
D. G.; Hewamadduma, C.; Sharrack, B.; Hadjivassiliou, M.; Chinnery,
P. F.; Dalton, A.; Shaw, P. J.: Clinical features of hereditary spastic
paraplegia due to spastin mutation. Neurology 67: 45-51, 2006. Note:
Erratum: Neurology 72: 1534 only, 2009.

18. McMonagle, P.; Byrne, P.; Hutchinson, M.: Further evidence of
dementia in SPG4-linked autosomal dominant hereditary spastic paraplegia. Neurology 62:
407-410, 2004.

19. McMonagle, P.; Byrne, P. C.; Fitzgerald, B.; Webb, S.; Parfrey,
N. A.; Hutchinson, M.: Phenotype of AD-HSP due to mutations in the
SPAST gene: comparison with AD-HSP without mutations. Neurology 55:
1794-1800, 2000.

20. Meijer, I. A.; Hand, C. K.; Cossette, P.; Figlewicz, D. A.; Rouleau,
G. A.: Spectrum of SPG4 mutations in a large collection of North
American families with hereditary spastic paraplegia. Arch. Neurol. 59:
281-286, 2002.

21. Mitne-Neto, M.; Kok, F.; Beetz, C.; Pessoa, A.; Bueno, C.; Graciani,
Z.; Martyn, M.; Monteiro, C. B. M.; Mitne, G.; Hubert, P.; Nygren,
A. O. H.; Valadares, M.; Cerqueira, A. M. P.; Starling, A.; Deufel,
T.; Zatz, M.: A multi-exonic SPG4 duplication underlies sex-dependent
penetrance of hereditary spastic paraplegia in a large Brazilian pedigree. Europ.
J. Hum. Genet. 15: 1276-1279, 2007.

22. Miura, S.; Shibata, H.; Kida, H.; Noda, K.; Toyama, T.; Iwasaki,
N.; Iwaki, A.; Ayabe, M.; Aizawa, H.; Taniwaki, T.; Fukumaki, Y.:
Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia
type 4 family. Neurogenetics 12: 25-31, 2011.

23. Murphy, S.; Gorman, G.; Beetz, C.; Byrne, P.; Dytko, M.; McMonagle,
P.; Kinsella, K.; Farrell, M.; Hutchinson, M.: Dementia in SPG4 hereditary
spastic paraplegia: clinical, genetic, and neuropathologic evidence. Neurology 73:
378-384, 2009.

24. Nance, M. A.; Raabe, W. A.; Midani, H.; Kolodny, E. H.; David,
W. S.; Megna, L.; Pericak-Vance, M. A.; Haines, J. L.: Clinical heterogeneity
of familial spastic paraplegia linked to chromosome 2p21. Hum. Hered. 48:
169-178, 1998.

25. Nielsen, J. E.; Koefoed, P.; Abell, K.; Hasholt, L.; Eiberg, H.;
Fenger, K.; Niebuhr, E.; Sorensen, S. A.: CAG repeat expansion in
autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24. Hum.
Molec. Genet. 6: 1811-1816, 1997.

26. Nielsen, J. E.; Krabbe, K.; Jennum, P.; Koefoed, P.; Jensen, L.
N.; Fenger, K.; Eiberg, H.; Hasholt, L.; Werdelin, L.; Sorensen, S.
A.: Autosomal dominant pure spastic paraplegia: a clinical, paraclinical,
and genetic study. J. Neurol. Neurosurg. Psychiat. 64: 61-66, 1998.

27. Orlacchio, A.; Gaudiello, F.; Totaro, A.; Floris, R.; St George-Hyslop,
P. H.; Bernardi, G.; Kawarai, T.: A new SPG4 mutation in a variant
form of spastic paraplegia with congenital arachnoid cysts. Neurology 62:
1875-1878, 2004.

28. Orlacchio, A.; Kawarai, T.; Totaro, A.; Errico, A.; St George-Hyslop,
P. H.; Rugarli, E. I.; Bernardi, G.: Hereditary spastic paraplegia:
clinical genetic study of 15 families. Arch. Neurol. 61: 849-855,
2004.

29. Orlacchio, A.; Patrono, C.; Gaudiello, F.; Rocchi, C.; Moschella,
V.; Floris, R.; Bernardi, G.; Kawarai, T.: Silver syndrome variant
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SPG4. Neurology 70: 1959-1966, 2008.

30. Reid, E.; Grayson, C.; Rubinsztein, D. C.; Rogers, M. T.; Rubinsztein,
J. S.: Subclinical cognitive impairment in autosomal dominant 'pure'
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32. Scott, W. K.; Gaskell, P. C.; Lennon, F.; Wolpert, C. M.; Menold,
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dominant familial spastic paraplegia. Neurogenetics 1: 95-102, 1997.

33. Shoukier, M.; Neesen, J.; Sauter, S. M.; Argyriou, L.; Doerwald,
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34. Starling, A.; Rocco, P.; Passos-Bueno, M. R.; Hazan, J.; Marie,
S. K.; Zatz, M.: Autosomal dominant (AD) pure spastic paraplegia
(HSP) linked to locus SPG4 affects almost exclusively males in a large
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35. Svenson, I. K.; Ashley-Koch, A. E.; Gaskell, P. C.; Riney, T.
J.; Cumming, W. J. K.; Kingston, H. M.; Hogan, E. L.; Boustany, R.-M.
N.; Vance, J. M.; Nance, M. A.; Pericak-Vance, M. A.; Marchuk, D.
A.: Identification and expression analysis of spastin gene mutations
in hereditary spastic paraplegia. Am. J. Hum. Genet. 68: 1077-1085,
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J. Y.; Hisanaga, S.; Pericak-Vance, M. A.; Ashley-Koch, A. E.; Marchuk,
D. A.: Intragenic modifiers of hereditary spastic paraplegia due
to spastin gene mutations. Neurogenetics 5: 157-164, 2004.

37. White, K. D.; Ince, P. G.; Lusher, M.; Lindsey, J.; Cookson, M.;
Bashir, R.; Shaw, P. J.; Bushby, K. M. D.: Clinical and pathologic
findings in hereditary spastic paraparesis with spastin mutation. Neurology 55:
89-94, 2000.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Nystagmus (rare)

GENITOURINARY:
[Bladder];
Urinary urgency;
Urinary incontinence;
Sphincter disturbances

SKELETAL:
[Spine];
Lower back pain

NEUROLOGIC:
[Central nervous system];
Lower limb spasticity;
Lower limb weakness;
Spastic gait;
Hyperreflexia;
Extensor plantar responses;
Pyramidal signs;
Degeneration of the lateral corticospinal tracts;
Cognitive decline;
Memory impairment;
Deficits in language expression;
Deficits in abstraction;
Mental retardation (rare);
Dementia (rare);
Arachnoid cysts of the cerebellopontine angle (reported in 1 family);
[Peripheral nervous system];
Decreased vibratory sense in the lower limbs;
[Behavioral/psychiatric manifestations];
Agitation;
Aggression;
Apathy;
Depression;
Disinhibition

MISCELLANEOUS:
Variable age of onset (infancy to 63 years);
Insidious onset;
Progressive disorder;
Highly variable severity;
Genetic anticipation;
Most common form of autosomal dominant hereditary spastic paraplegia
(accounts for 40% of SPG cases);
Genetic heterogeneity, see SPG3A (182600)

MOLECULAR BASIS:
Caused by mutation in the spastin gene (SPG4, 604277.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 1/26/2005
Cassandra L. Kniffin - updated: 8/30/2004
Cassandra L. Kniffin - revised: 9/27/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/24/2012
joanna: 6/11/2007
ckniffin: 6/8/2007
ckniffin: 1/26/2005
ckniffin: 8/30/2004
joanna: 10/23/2002
ckniffin: 10/23/2002
ckniffin: 9/30/2002
ckniffin: 9/27/2002
alopez: 9/21/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 2/12/2013
Cassandra L. Kniffin - updated: 12/17/2009
Cassandra L. Kniffin - updated: 8/28/2009
Cassandra L. Kniffin - updated: 10/1/2008
Cassandra L. Kniffin - updated: 3/19/2008
Cassandra L. Kniffin - updated: 8/20/2007
Cassandra L. Kniffin - updated: 7/24/2007
Cassandra L. Kniffin - updated: 4/27/2007
Cassandra L. Kniffin - updated: 2/6/2007
Cassandra L. Kniffin - updated: 4/11/2006
Cassandra L. Kniffin - updated: 1/26/2005
Cassandra L. Kniffin - updated: 10/26/2004
Cassandra L. Kniffin - updated: 8/30/2004
Cassandra L. Kniffin - updated: 7/27/2004
Cassandra L. Kniffin - updated: 12/27/2002
Cassandra L. Kniffin - reorganized: 10/4/2002
Cassandra L. Kniffin - updated: 6/26/2002
Victor A. McKusick - updated: 6/15/2001
George E. Tiller - updated: 4/14/2000
Michael J. Wright - updated: 1/19/2000
Victor A. McKusick - updated: 11/2/1998
Victor A. McKusick - updated: 10/2/1998
Victor A. McKusick - updated: 8/17/1998
Victor A. McKusick - updated: 7/7/1998
Victor A. McKusick - updated: 5/5/1998
Victor A. McKusick - updated: 11/4/1997
Victor A. McKusick - updated: 5/30/1997

*FIELD* CD
Victor A. McKusick: 10/14/1993

*FIELD* ED
tpirozzi: 08/14/2013
tpirozzi: 8/14/2013
tpirozzi: 8/13/2013
terry: 3/15/2013
carol: 3/11/2013
alopez: 2/18/2013
ckniffin: 2/12/2013
wwang: 3/2/2011
wwang: 1/8/2010
ckniffin: 12/17/2009
wwang: 9/14/2009
ckniffin: 8/28/2009
wwang: 11/11/2008
wwang: 10/3/2008
ckniffin: 10/1/2008
wwang: 4/10/2008
ckniffin: 3/19/2008
wwang: 9/6/2007
ckniffin: 8/20/2007
wwang: 8/3/2007
ckniffin: 7/24/2007
wwang: 6/8/2007
ckniffin: 4/27/2007
wwang: 2/8/2007
ckniffin: 2/6/2007
wwang: 4/20/2006
ckniffin: 4/11/2006
terry: 6/24/2005
tkritzer: 2/2/2005
ckniffin: 1/26/2005
tkritzer: 11/1/2004
ckniffin: 10/26/2004
carol: 9/7/2004
ckniffin: 8/30/2004
tkritzer: 7/28/2004
ckniffin: 7/27/2004
carol: 1/6/2003
ckniffin: 12/27/2002
carol: 10/4/2002
ckniffin: 9/30/2002
tkritzer: 8/9/2002
ckniffin: 6/26/2002
cwells: 6/27/2001
terry: 6/15/2001
alopez: 4/17/2000
terry: 4/14/2000
alopez: 1/19/2000
alopez: 11/9/1999
alopez: 11/2/1999
mgross: 9/24/1999
carol: 11/11/1998
terry: 11/2/1998
dkim: 10/12/1998
carol: 10/7/1998
terry: 10/2/1998
carol: 8/18/1998
terry: 8/17/1998
carol: 7/9/1998
terry: 7/7/1998
carol: 5/12/1998
terry: 5/5/1998
jenny: 11/12/1997
terry: 11/4/1997
alopez: 7/29/1997
terry: 7/7/1997
jenny: 6/3/1997
terry: 5/30/1997
mimadm: 3/25/1995
carol: 1/23/1995
terry: 11/16/1994
carol: 10/14/1993

MIM 604277
*RECORD*
*FIELD* NO
604277
*FIELD* TI
*604277 SPASTIN; SPAST
;;SPG4 GENE; SPG4
*FIELD* TX

CLONING

Using a positional cloning strategy based on the spastic paraplegia-4
read more(SPG4; 182601) candidate region on chromosome 2p22-p21, Hazan et al.
(1999) identified a gene encoding a member of the AAA protein family
(see 601681) that they named 'spastin' (SPAST). The spastin open reading
frame encodes a 616-amino acid protein of approximately 67.2 kD. The AAA
cassette is located between amino acids 342 and 599. The 3 conserved
ATPase domains include Walker motifs A and B. Spastin and related
members of its AAA subgroup contain leucine zipper motifs, which in
spastin occur at amino acid positions 50-78 and 508-529. The spastin C
terminus has strong homology to several members of the AAA family.
Comparison of amino acid sequences of spastin and mitochondrial
metalloproteinases showed that homology is restricted to the AAA
cassette. Spastin shows only 29% identity between amino acid positions
342 and 599 with paraplegin (602783); paraplegin shows 57% identity with
yeast Afg3p over the same region, suggesting that spastin does not
belong to the same AAA subfamily as do paraplegin and other
metalloproteinases. SPG4 is ubiquitously expressed in human adult and
fetal tissue, showing slightly higher expression in fetal brain.

Hazan et al. (1999) cloned the mouse ortholog of SPAST, which between
amino acids 113 and 616 has 96% identity with human SPAST. Spast
transcripts are ubiquitously expressed in adult tissues and from
embryonic day 7 to 17 in mouse.

GENE STRUCTURE

Hazan et al. (1999) determined that the SPAST gene occupies
approximately 90 kb of genomic DNA and contains 17 putative exons.

GENE FUNCTION

By expressing wildtype or ATPase-defective spastin in several cell
types, Errico et al. (2002) showed that spastin interacts with
microtubules. Interaction with the cytoskeleton was mediated by the
N-terminal region of spastin and was regulated through the ATPase
activity of the AAA domain. Expression of missense mutations (including
604277.0001, 604277.0002, and 604277.0004) into the AAA domain led to
constitutive binding to microtubules in transfected cells and induced
the disappearance of the aster and the formation of thick perinuclear
bundles, suggesting a role of spastin in microtubule dynamics.
Consistently, wildtype spastin promoted microtubule disassembly in
transfected cells. The authors suggested that spastin may be involved in
microtubule dynamics similarly to the highly homologous
microtubule-severing protein katanin (606696). The authors hypothesized
that impairment of fine regulation of the microtubule cytoskeleton in
long axons, due to spastin mutations, may underlie the pathogenesis of
hereditary spastic paraplegia.

By multiple sequence alignment, Ciccarelli et al. (2003) identified a
domain of approximately 80 amino acids shared by spastin and spartin
(607111), the molecule that is mutated in the Amish type of hereditary
spastic paraplegia (SPG20; 275900). The domain is a slightly expanded
version of a domain that is a well established and consistent feature of
molecules with a role in endosomal trafficking. Both spastin and spartin
are likely to be involved in microtubule interaction. Ciccarelli et al.
(2003) proposed a new descriptive name MIT (contained within
microtubule-interacting and trafficking molecules) for the domain and
predicted endosomal trafficking as the principal functionality of all
molecules in which it is present.

In neuronal and nonneuronal cells expressing spastin, McDermott et al.
(2003) found that the wildtype protein was localized to the perinuclear
area within the cell soma, whereas mutant spastin was found throughout
the cytoplasm consistent with cytoskeletal staining, as well as
extending into the axons, but not the dendrites. Transfection of
proteins into the cells suggested that normal spastin acts as a
microtubule-severing protein and that mutant spastin colocalizes with,
but does not sever, microtubules. The abnormal interaction of mutant
spastin with microtubules was associated with abnormal cellular
distribution of mitochondria and peroxisomes. McDermott et al. (2003)
suggested that the disruption of organelle transport on the microtubule
cytoskeleton, including transport to distal axons, may be the primary
disease mechanism in SPG4.

Errico et al. (2004) demonstrated that spastin was enriched in cell
regions containing dynamic microtubules. During cell division spastin
was found in the spindle pole, the central spindle, and the midbody,
whereas in immortalized motoneurons it was enriched in the distal axon
and the branching points. Spastin interacted with the centrosomal
protein NA14 (SSNA1; 610882), and cofractionated with gamma-tubulin
(TUBG1; 191135). Deletion of the region required for binding to NA14
disrupted spastin interaction with microtubules, suggesting that NA14
may be an important adaptor to target spastin activity at the
centrosome. Errico et al. (2004) hypothesized that spastin may play a
role in cytoskeletal rearrangements and dynamics.

Using a yeast 2-hybrid approach, Reid et al. (2005) identified CHMP1B
(606486), a protein associated with the ESCRT (endosomal sorting complex
required for transport)-III complex, as a binding partner of spastin.
CHMP1B and spastin proteins showed clear cytoplasmic colocalization in
transfected cells; CHMP1B and spastin proteins interacted specifically
in vitro and in vivo in complementation assays, and spastin
coimmunoprecipitated with CHMP1B. The interaction was mediated by a
region of spastin lying between residues 80 and 196 and containing an
MIT domain. Expression of epitope-tagged CHMP1B in mammalian cells
prevented the development of the abnormal microtubule phenotype
associated with expression of ATPase-defective spastin. The authors
suggested a role for spastin in intracellular membrane traffic events,
and proposed that defects in intracellular membrane traffic may be a
significant cause of motor neuron pathology.

Svenson et al. (2005) developed a novel antiserum corresponding to a
portion of exon 6 of the SPG4 gene that was specific for all spastin
isoforms. Using this reagent, the authors found that endogenous spastin
was located at the centrosome in a variety of cell types at all points
in the cell cycle. Spastin remained localized at the centrosome even
after microtubule depolymerization, suggesting that spastin is an
integral centrosomal protein. Spastin was also enriched at discrete
clusters in dendrites, axons, and glial projections of rat hippocampal
neurons. Svenson et al. (2005) concluded that spastin plays a role in
microtubule dynamics and organization.

Independently, Evans et al. (2006) and Sanderson et al. (2006)
demonstrated that the N-terminal domain of spastin bound directly to the
C-terminal cytoplasmic domain of atlastin (ATL1; 606439), suggesting
that the 2 gene products interact in a common biologic pathway. Evans et
al. (2006) used yeast 2-hybrid analysis and coimmunoprecipitation
studies in HeLa cells, and Sanderson et al. (2006) used yeast 2-hybrid
analysis of a human fetal brain cDNA library and protein pull-down,
coimmunoprecipitation, and colocalization studies in HeLa cells, HEK293T
cells, and mouse NSC34 neuronal cells.

By yeast 2-hybrid analysis and coimmunoprecipitation studies in mouse
fibroblast cells (NIH3T3) and HeLa cells, Mannan et al. (2006)
demonstrated that spastin interacts with reticulon-1 (RTN1; 600865),
which is primarily expressed in the endoplasmic reticulum. The
interaction is mediated through the spastin N-terminal region, which
contains a microtubule-interacting and trafficking domain. Intracellular
distribution studies showed colocalization of the 2 proteins in discrete
cytoplasmic vesicles. The findings strengthened the hypothesis that
disruption of intracellular vesicular transport processes may underlie
spastic paraplegia.

Using immunoprecipitation studies, Montenegro et al. (2012) showed that
spastin interacted with RTN2B (603183). Cellular expression of
ATPase-defective spastin redistributed the ER onto abnormally thickened
and elongated microtubule bundles, and RTN2B was also redistributed onto
these bundles. The findings indicated that RTN2 participates in the
network of hairpin loop-containing ER morphogens, including REEP1
(609139), atlastin-1 (ATL1; 606439), and spastin.

BIOCHEMICAL FEATURES

- Crystal Structure

Roll-Mecak and Vale (2008) reported the x-ray crystal structure of the
Drosophila spastin AAA domain and provided a model for the active
spastin hexamer generated using small-angle x-ray scattering combined
with atomic docking. The spastin hexamer forms a ring with a prominent
central pore and 6 radiating arms that may dock onto the microtubule.
Helices unique to the microtubule-severing AAA ATPases surround the
entrances to the pore on either side of the ring, and 3 highly conserved
loops line the pore lumen. Mutagenesis revealed essential roles for
these structural elements in the severing reaction. Peptide and antibody
inhibition experiments further showed that spastin may dismantle
microtubules by recognizing specific features in the carboxy-terminal
tail of tubulin. Roll-Mecak and Vale (2008) concluded that their data
supported a model in which spastin pulls the C terminus of tubulin
through its central pore, generating a mechanical force that
destabilizes tubulin-tubulin interactions within the microtubule
lattice.

MOLECULAR GENETICS

Hazan et al. (1999) amplified and sequenced overlapping cDNA fragments
spanning the entire spastin open reading frame from 1 individual of each
of 14 families affected with SPG4 and 6 control individuals. Using this
technique, they identified heterozygous mutations in 5 families (see
604277.0001-604277.0005). Three unrelated affected individuals
originating from the same area in Switzerland were heterozygous for a
mutation in the acceptor splice site of SPG4 intron 15 (604277.0005).

Fonknechten et al. (2000) analyzed DNA from 87 unrelated autosomal
dominant hereditary spastic paraplegia patients and detected 34 novel
mutations scattered along the coding region of the SPG4 gene (see, e.g.,
604277.0007 and 604277.0008). They found missense (28%), nonsense (15%),
and splice site point (26.5%) mutations as well as deletions (23%) and
insertions (7.5%). Six percent of 238 mutation carriers were
asymptomatic, while 20% of carriers were unaware of their symptoms,
indicating reduced penetrance. There was no difference in either age of
onset or clinical severity among groups of patients with missense
mutations versus truncation mutations.

Using the repeat expansion detection (RED) method, Nielsen et al. (1997)
analyzed 21 affected individuals from 6 SPG4 Danish families linked to
2p24-p21. They found that 20 of 21 affected individuals showed CAG
repeat expansions of the SPG4 gene versus 2 of 21 healthy spouses,
suggesting a strongly statistically significant association between the
occurrence of the repeat expansion and the disease. Hazan et al. (1999),
however, constructed a detailed high-resolution integrated map of the
SPG4 locus that excluded the involvement of a CAG repeat expansion in
SPG4-linked autosomal dominant spastic paraplegia. They noted that an
analysis of 20 autosomal dominant hereditary spastic paraplegia
families, including 4 linked to the SPG4 locus, by Benson et al. (1998)
had demonstrated that most repeat expansions detected by the RED method
were caused by nonpathogenic expansions at the 18q21.1 SEF2 (602272) and
17q21.3 ERDA1 (603279) loci.

Burger et al. (2000) identified 4 novel SPG4 mutations in German
families with autosomal dominant hereditary spastic paraplegia,
including 1 large family for which anticipation had been proposed
(Burger et al., 1996). Since no trinucleotide repeat expansion was found
in this family but instead a D441G missense mutation (604277.0009), the
authors presumed that the clinically observed anticipation was due to
ascertainment bias.

Svenson et al. (2001) screened the spastin gene for mutations in 15
families consistent with linkage to the SPG4 locus and identified 11
mutations, 10 of which were novel (see, e.g., 604277.0011-604277.0012).
Five of the mutations were in noninvariant splice junction sequences.
RT-PCR analysis of mRNA from patients showed that each of these 5
mutations resulted in aberrant splicing. One mutation was found to be
'leaky,' or partially penetrant; the mutant allele produced both mutant
(skipped exon) and wildtype (full-length) transcripts. The existence of
at least one leaky mutation suggested that relatively small differences
in the level of wildtype spastin expression can have significant
functional consequences. This may account, at least in part, for the
wide ranges in age at onset, symptom severity, and rate of symptom
progression that occurs both among and within families with SPG linked
to SPG4.

Sauter et al. (2002) analyzed the spastin gene in SPG patients from 161
apparently unrelated families in Germany and identified mutations in 27
of the families. Only 3 of the mutations had previously been described
and only 1 of the mutations was found in 2 families. Among the detected
mutations were 14 frameshift, 4 nonsense, and 4 missense mutations, 1
large deletion spanning several exons, and 4 splice mutations. Most of
the novel mutations were located in the conserved AAA cassette-encoding
region of the spastin gene. The relative frequency of spastin gene
mutations in an unselected group of German hereditary spastic paraplegia
patients was approximately 17%; frameshift mutations accounted for most
SPG4 mutations in the population. The proportion of splice mutations was
considerably lower than that reported elsewhere (Lindsey et al., 2000;
Svenson et al., 2001).

In 15 of 76 unrelated individuals from North America with hereditary
spastic paraplegia (HSP), Meijer et al. (2002) identified 5 previously
reported mutations and 8 novel mutations in the SPG4 gene: 4 missense, 1
nonsense, 1 frameshift, and 2 splice site mutations.

Charvin et al. (2003) used anti-spastin polyclonal antibodies to
identify 2 isoforms of 75 and 80 kD in both human and mouse tissues,
with a tissue-specific variability of the isoform ratio. Spastin is an
abundant protein in neural tissues and immunofluorescence microscopy
analysis revealed expression in neurons but not in glial cells. These
data suggested that axonal degeneration linked to SPG4 mutations may be
caused by a primary defect of neurons. Protein and transcript analyses
of patients carrying either nonsense or frameshift SPG4 mutations
revealed neither truncated protein nor mutated transcripts, providing
further evidence that these mutations are responsible for a loss of
spastin function.

Svenson et al. (2004) identified 2 rare polymorphisms in the SPG4 gene:
ser44 to leu (S44L; 604277.0015) and pro45 to gln (P45Q; 604277.0017).
In affected members of 4 SPG4 families, the presence of either the S44L
or P45Q polymorphism in addition to a disease-causing SPG4 mutation
(see, e.g., 604277.0016; 604277.0018) resulted in an earlier age at
disease onset. Svenson et al. (2004) concluded that the S44L and P45Q
polymorphisms, though benign alone, modified the SPG4 phenotype when
present with another SPG4 mutation.

In 8 of 18 Korean patients with spastic paraplegia, Park et al. (2005)
identified 8 different mutations in the SPG4 gene. Seven of the 8
patients had a family history of the disorder. No mutations were
identified in the SPG3A gene (ATL1; 606439).

Brugman et al. (2005) identified 6 mutations in the SPG4 gene in 6 (13%)
of 47 unrelated patients with adult-onset upper motor neuron symptoms
restricted to the legs. A seventh SPG4 mutation was identified in a
34-year-old woman with rapidly progressive spastic tetraparesis and
pseudobulbar dysarthria consistent with a diagnosis of amyotrophic
lateral sclerosis (ALS; see 105400). However, no spastin mutations were
identified in 51 additional patients with upper motor neuron involvement
of the arms or bulbar regions, suggesting that spastin mutations are not
a common cause of ALS.

In 13 (26%) of 50 unrelated Italian patients with pure hereditary
spastic paraplegia (HSP), Crippa et al. (2006) identified 12 different
mutations in the SPG4 gene, including 8 novel mutations. All 5 of the
familial cases analyzed carried an SPG4 mutation, confirming that the
most common form of autosomal dominant HSP is caused by mutations in
this gene. Eight (18%) of 45 sporadic patients had an SPG4 mutation. No
mutations were identified in 10 additional patients with complicated
HSP. Genotype-phenotype correlations were not observed.

In 24 (20%) of 121 probands with autosomal dominant SPG in whom
mutations in the SPG4 gene were not detected by DHPLC, Depienne et al.
(2007) identified 16 different heterozygous exonic deletions in the SPG4
gene using multiplex ligation-dependent probe amplification (MLPA). The
deletions ranged in size from 1 exon to the whole coding sequence. The
patients with deletions showed a similar clinical phenotype as those
with point mutations but an earlier age at onset. The findings confirmed
that haploinsufficiency of SPG4 is a major cause of autosomal dominant
SPG and that exonic deletions account for a large proportion of
mutation-negative SPG4 patients, justifying the inclusion of gene dosage
studies in appropriate clinical scenarios. Depienne et al. (2007) stated
that over 150 different pathogenic mutations in the SPG4 gene had been
identified to date.

McDermott et al. (2006) identified 44 different mutations in the SPG4
gene, including 27 novel mutations, in 53 (19%) of 285 individuals with
spastic paraplegia. The majority of mutations occurred within the
conserved AAA cassette or were predicted to cause premature termination
or missplicing within the AAA cassette. The heterozygous S44L change was
identified in 8 (2.8%) of 285 SPG individuals and in 3.1% of healthy
controls, indicating that it is a polymorphism.

Beetz et al. (2006) identified partial deletions in the SPG4 gene in 12
(18%) of 65 patients with spastic paraplegia who had previously been
regarded as spastin mutation-negative based on direct sequencing. The
authors suggested that partial spastin deletions act via
haploinsufficiency. Using MLPA analysis, Beetz et al. (2007) identified
partial deletions of the SPG4 gene in 7 of 8 families who had been
linked to the region, but in whom mutation screening had not identified
mutations. The families had been previously reported by Lindsey et al.
(2000), McMonagle et al. (2000), Meijer et al. (2002), and Svenson et
al. (2001). The findings indicated that large genomic deletions in SPG4
are not uncommon and should be part of a workup for autosomal dominant
SPG.

Beetz et al. (2007) reported a family in which spastic paraplegia
segregated with a deletion of exon 1 of the SPG4 gene in the proband,
her brother, and her 2 sons. Although the proband and her brother also
had a deletion of the SPG3A gene, the SPG3A deletion did not segregate
with the disorder in her sons and had no apparent effect on the severity
of the disorder. The findings suggested that haploinsufficiency is the
pathogenic mechanism for SPG4, whereas a dominant-negative effect is the
pathogenic mechanism for SPG3A.

Shoukier et al. (2009) identified SPG4 mutations in 57 (28.5%) of 200
unrelated, mostly German patients with SPG. There were 47 distinct
mutations identified, including 29 novel mutations. In a review of other
reported mutations, the authors found that most (72.7%) of the mutations
were clustered in the C-terminal AAA domain. However, clustering was
also observed in the MIT domain, MTBD, and an N-terminal region
(residues 228 to 269). In the original cohort of 57 patients, there was
a tentative genotype-phenotype correlation indicating that missense
mutations were associated with an earlier onset of the disease.

GENOTYPE/PHENOTYPE CORRELATIONS

Ivanova et al. (2006) identified 5 different heterozygous mutations in
the SPG4 gene in 6 of 36 unrelated Bulgarian patients with hereditary
spastic paraplegia. All 6 probands with SPG4 mutations had affected
family members. There were 2 missense mutations, 1 premature
termination, and 2 splice site mutations. Affected individuals with the
missense mutations had a significantly earlier mean age at onset (4.5 to
8 years) compared to the other patients (17.5 to 42.5 years). In
addition, 3 affected members of 1 of the families with a missense
mutation also had scoliosis. Ivanova et al. (2006) predicted that the
splice site and truncation mutations decreased overall spastin function,
implying haploinsufficiency as a pathogenic mechanism, whereas the
missense mutations likely resulted in a dominant-negative pathogenic
mechanism and a more severe phenotype.

*FIELD* AV
.0001
SPASTIC PARAPLEGIA 4
SPAST, SER362CYS

In a member of a family with spastic paraplegia-4 (182601), Hazan et al.
(1999) identified a C-to-G transversion at nucleotide 1210 in exon 7 of
the SPAST gene, resulting in a ser362-to-cys (S362C) substitution.

.0002
SPASTIC PARAPLEGIA 4
SPAST, CYS448TYR

In a member of a family with spastic paraplegia-4 (182601), Hazan et al.
(1999) identified a G-to-A transition at nucleotide 1468 in exon 11 of
the SPAST gene, resulting in a cys448-to-tyr (C448Y) amino acid change.

.0003
SPASTIC PARAPLEGIA 4
SPAST, 1-BP DEL, 1520T

In a member of a family with spastic paraplegia-4 (182601), Hazan et al.
(1999) identified a single basepair deletion, of a T at nucleotide
position 1520 in exon 11 of the SPAST gene, which would result in a
premature termination codon at amino acid position 466. If stable, this
protein would be truncated at 465 amino acids.

.0004
SPASTIC PARAPLEGIA 4
SPAST, ARG499CYS

In a member of a family with spastic paraplegia-4 (182601), Hazan et al.
(1999) identified a C-to-T transition at nucleotide 1620 in exon 13 of
the SPAST gene resulting in an arginine-to-cysteine substitution at
codon 499 (R499C). This mutation was identified in family 618.

The same mutation was found by Svenson et al. (2001) in a set of 11
mutations found in 15 families with SPG4, the other 10 of which were
novel.

.0005
SPASTIC PARAPLEGIA 4
SPAST, 1813, A-G, -2

In 3 unrelated individuals from 3 kindreds with autosomal dominant
spastic paraplegia-4 (182601), Hazan et al. (1999) identified a
heterozygous A-to-G mutation in the acceptor splice site of intron 15 of
the SPAST gene, resulting in the skipping of exon 16 followed by
subsequent frameshift in the aberrant transcript. Each of the
individuals originated from the same area of Switzerland, suggesting
that these kindreds have a common ancestor.

.0006
REMOVED FROM DATABASE
.0007
SPASTIC PARAPLEGIA 4
SPAST, LYS229TER

In a member of a family with spastic paraplegia-4 (182601), Fonknechten
et al. (2000) identified an A-to-T transversion at nucleotide 873 in
exon 5 of the SPAST gene, resulting in a premature termination codon at
amino acid position 229 (lys229 to ter; K229X).

.0008
SPASTIC PARAPLEGIA 4
SPAST, 1-BP INS, 578A

In a member of a family with spastic paraplegia-4 (182601), Fonknechten
et al. (2000) identified a single base insertion of A after nucleotide
578 in exon 2 of the SPAST gene, resulting in a premature termination
codon 2 amino acids downstream from the insertion.

.0009
SPASTIC PARAPLEGIA 4
SPAST, ASP441GLY

In a family with autosomal dominant spastic paraplegia (182601), Burger
et al. (2000) used direct sequencing of the PCR product corresponding to
exon 11 to demonstrate heterozygosity for an A-to-G substitution at the
first nucleotide of the exon. This alteration caused an aspartic
acid-to-glycine exchange (asp441 to gly; D441G) in the Walker B motif of
the peptide. Within this motif of 6 amino acids (IIFIDE), the fifth
position is D (aspartic acid) in 8 known proteins that exhibit high
homology to spastin (Hazan et al., 1999). Aspartic acid is very polar
and thus nearly always found on the outside of proteins, whereas glycine
is nonpolar and tends to be on the inside.

.0010
SPASTIC PARAPLEGIA 4
SPAST, IVS16DS, G-C, +1

In a 5-generation Italian family with pure autosomal dominant spastic
paraplegia (182601) that showed marked intrafamilial variability in both
age of onset and clinical severity, ranging from severe congenital
presentation to mild involvement after age 55, Santorelli et al. (2000)
identified a G-to-C substitution at nucleotide 1853+1 of the SPAST gene.
This heterozygous mutation alters the consensus donor splice site of
SPAST intron 16, resulting in an aberrant transcript with a longer exon
16 and a premature termination codon at amino acid 578. This produces a
protein shortened by 38 amino acids in its conserved C terminus,
removing part of the spastin AAA cassette (amino acids 577-599) and
presumably causing loss of function.

.0011
SPASTIC PARAPLEGIA 4
SPAST, IVS9, A-G, +4

Svenson et al. (2001) found a splice site mutation (ivs9+4A-G) in an
affected member of a family with SPG4 (182601). This 'leaky,' or
partially penetrant, mutation was present in heterozygous state. A
full-length, normally spliced transcript as well as an abnormally
spliced transcript was produced from the mutant allele of the patient.

.0012
SPASTIC PARAPLEGIA 4
SPAST, 1-BP INS, T, IVS11, +2

Svenson et al. (2001) described another 'leaky' mutation, an IVS11+2T
insertion, in a patient with SPG4 (182601), causing skipping of exon 11
in the SPAST gene. This insertion would shift the basepairing by 1
nucleotide, resulting in a net loss of 4 basepairs relative to the
pairing with the wildtype sequence. Despite this drastic alteration in
heterogeneous nuclear RNA pairing, this mutation, in its full
genomic-sequence context, is only partially penetrant. Both normally and
aberrantly spliced transcripts were produced from the mutant allele.

.0013
SPASTIC PARAPLEGIA 4
SPAST, ILE344LYS

In a Korean family with typical clinical features of pure autosomal
dominant hereditary spastic paraplegia-4 (182601), Ki et al. (2002)
found a novel T-to-A substitution at nucleotide 1031 in exon 7 of the
spastin gene. The alteration caused an ile334-to-lys (I344K) mutation
which affected the third amino acid of the highly conserved AAA cassette
domain.

.0014
SPASTIC PARAPLEGIA 4
SPAST, ASN386SER

In affected members of 9 families with SPG4 (182601) originating from
southern Scotland, Orlacchio et al. (2004) identified a heterozygous
1157A-G transition in exon 8 of the SPAST gene, resulting in an
asn386-to-ser (N386S) substitution. Haplotype analysis suggested a
founder effect. The N386S mutation is located within a conserved region
in the spastin Walker motif A. In vitro functional expression studies
showed that the mutant protein bound to a subset of microtubules which
were reorganized in thick perinuclear bundles.

.0015
SPASTIC PARAPLEGIA 4, MODIFIER OF
SPAST, SER44LEU

In a patient with a mild form of SPG4 (182601), Lindsey et al. (2000)
identified a homozygous 256C-T transition in exon 1 of the SPAST gene,
resulting in a ser44-to-leu (S44L) substitution. The patient had never
been able to run, but was otherwise asymptomatic until age 60 years,
when he began to have gait abnormalities and lower limb spasticity.
There was no family history of the disorder.

Svenson et al. (2004) found the L44 allele at a frequency of less than
0.6% (5 of 900 alleles) in a North American control population,
indicating that it is a rare polymorphism.

In affected individuals from 3 unrelated SPG4 families, Svenson et al.
(2004) identified compound heterozygosity for the S44L substitution and
another disease-causing mutation in the SPAST gene (see, e.g.,
604277.0016). Patients with both the disease-causing mutation and the
S44L change had a significantly earlier age at disease onset than
affected family members who carried only the disease-causing mutation.
Two individuals who carried only a single S44L allele were asymptomatic.
Using a bioinformatics approach, Svenson et al. (2004) found that the
highly conserved S44 residue is likely a phosphorylation target site of
cyclin-dependent kinases. The authors concluded that the S44L
polymorphism acts as a phenotypic modifier of SPG4.

In a female child with severe infantile-onset SPG4, Chinnery et al.
(2004) identified compound heterozygosity for 2 mutations in the SPAST
gene: S44L and a missense mutation. The proband's father, who was mildly
affected, had the S44L mutation; the mother, who was unaffected, and the
maternal grandfather, who was severely affected, had the other mutation.
Chinnery et al. (2004) concluded that the severe phenotype in the child
resulted from 2 codominant mutations. The authors also noted that the
mother remained unaffected despite having an SPAST mutation.

McDermott et al. (2006) identified a heterozygous S44L change in 2.8% of
SPG individuals and in 3.1% of healthy controls, indicating that it is a
polymorphism. Two of 3 individuals heterozygous for the S44L variant
showed lower motor neuron dysfunction on EMG examination. The authors
suggested that S44L may act as a weak mutation, causing a noncritical
reduction in spastin activity that only becomes clinically significant
when combined with another defect in motor neuron function.

.0016
SPASTIC PARAPLEGIA 4
SPAST, ASP470VAL

In 6 affected members spanning 3 generations of a family with SPG4
(182601), Svenson et al. (2004) identified a heterozygous 1534A-T
transversion in the SPAST gene, resulting in an asp470-to-val (D470V)
substitution. The 3 patients with only the heterozygous D470V mutation
had adult onset at ages 55, 40, and 18 years, respectively, whereas 3
patients who were compound heterozygous for the D470V mutation and the
S44L (604277.0015) polymorphism had disease onset in infancy, were
wheelchair-bound by age 40 years, had a stutter, and had mild to
moderate cognitive deficits. Svenson et al. (2004) concluded that
presence of the S44L polymorphism, in addition to the D470V mutation,
modified the SPG4 phenotype in this family.

.0017
SPASTIC PARAPLEGIA 4, MODIFIER OF
SPAST, PRO45GLN

Svenson et al. (2004) identified a 259C-A transversion in the SPAST
gene, resulting in a pro45-to-gln (P45Q) substitution, at a frequency of
less than 0.2% (1 of 900 alleles) in a North American control
population, indicating that it is a rare polymorphism.

In 2 affected members of a family with SPG4 (182601), Svenson et al.
(2004) identified compound heterozygosity for the P45Q polymorphism and
a disease-causing arg562-to-gly mutation in the SPAST gene (R562G;
604277.0018). These 2 patients had disease onset in infancy, whereas
affected members with only the disease-causing R562G mutation had
significantly later onset. Two family members who carried only the P45Q
polymorphism were unaffected. Svenson et al. (2004) concluded that the
P45Q polymorphism was a modifier of the SPG4 phenotype.

.0018
SPASTIC PARAPLEGIA 4
SPAST, ARG562GLY

In 11 affected members spanning 3 generations of a family with SPG4
(182601), Svenson et al. (2004) identified a heterozygous arg562-to-gly
(R562G) substitution in the SPAST gene. Two of the 11 patients, who were
compound heterozygous for the R562G mutation and the pro45-to-gln
polymorphism (P45Q; 604277.0017), had disease onset in infancy, whereas
7 of 9 patients who had only the D470V mutation had later onset at ages
ranging from 17 to 58 years. Two family members who carried only the
P45Q polymorphism were asymptomatic. The authors concluded that
inheritance of the P45Q polymorphism, when present with the
disease-causing R562G mutation, modified the SPG4 phenotype in this
family.

.0019
SPASTIC PARAPLEGIA 4
SPAST, 2.3-KB DEL

In 6 affected members of a Japanese family with a relatively mild form
of SPG4 (182601), Iwanaga et al. (2005) identified a heterozygous
2,307-bp deletion in the SPAST gene. The deletion spanned from the
5-prime UTR, 114-bp upstream of the translation initiation site, to
1.8-kb downstream of the exon 1 splice donor site. The results suggested
that the primary SPAST mRNA transcript lacked the entire coding region
of exon 1, including the translation initiation site and the donor site
of exon 1, leading to defective splicing and subsequent rapid mRNA
degradation. The structural abnormality was detected by Southern blot
analysis followed by deletion-specific PCR amplification.

.0020
SPASTIC PARAPLEGIA 4
SPAST, 30-BP DEL, NT1216

In a woman with SPG4 (182601), Schickel et al. (2006) identified a
heterozygous 1216A-G transition in exon 9 of the SPAST gene. Although
the mutation was predicted to result in an ile406-to-val (I406V)
substitution, RT-PCR and direct sequencing of lymphocyte-derived cDNA
revealed a 30-bp in-frame deletion of nucleotides 1216 to 1245 in exon
9, corresponding to deletion of codons 406 to 415. Thus, the 1216A-G
transition created a fully dominant ectopic splice donor site.
Transfection experiments in human cells showed that the mutant spastin
protein with the deletion showed normal subcellular localization but
lacked microtubule-severing activity, consistent with
haploinsufficiency. A mutant construct containing the I406V substitution
showed subcellular localization and microtubule-severing activity that
was similar to wildtype spastin protein, suggesting that the predicted
amino acid substitution was not pathogenic.

.0021
SPASTIC PARAPLEGIA 4
SPAST, SER445ARG

In a patient with a severe form of SPG4 (182601), McDermott et al.
(2006) identified a 1335C-A transversion in exon 11 of the SPAST gene,
resulting in a ser445-to-arg (S445R) substitution. He developed walking
difficulties in his late teens with deteriorating gait in his 20s; he
was wheelchair-dependent at age 35. He later developed stiffness in the
upper limbs, bladder dysfunction, dysarthria, and swallowing
difficulties. In his 40s, he developed respiratory insufficiency and
distal muscle wasting in the lower limbs. The findings of bulbar and
respiratory involvement, as well as lower motor neuron degeneration,
broadened the phenotype associated with mutations in the SPAST gene.

.0022
SPASTIC PARAPLEGIA 4
SPAST, EX10-EX12, DUP

In affected individuals of a large Brazilian kindred with SPG4 (182601),
originally reported by Starling et al. (2002), Mitne-Neto et al. (2007)
identified a heterozygous tandem duplication of exons 10 through 12 of
the SPAST gene. Long-range PCR and sequencing showed nonhomology of the
sequences contributing to the novel fusion. The duplication was
predicted to result in premature termination and disruption of enzymatic
activity. Twelve of 30 mutation carriers had no clinical complaints.
Among these patients, 9 of 14 female carriers had no complaints,
indicating sex-dependent penetrance in this family, with women being
partially protected.

*FIELD* RF
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gene deletion neither co-segregates with disease nor modifies phenotype
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2. Beetz, C.; Nygren, A. O. H.; Schickel, J.; Auer-Grumbach, M.; Burk,
K.; Heide, G.; Kassubek, J.; Klimpe, S.; Klopstock, T.; Kreuz, F.;
Otto, S.; Schule, R.; Schols, L.; Sperfeld, A.-D.; Witte, O. W.; Deufel,
T.: High frequency of partial SPAST deletions in autosomal dominant
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3. Beetz, C.; Zuchner, S.; Ashley-Koch, A.; Auer-Grumbach, M.; Byrne,
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Schickel, J.; Shaw, P. J.; Deufel, T.: Linkage to a known gene but
no mutation identified: comprehensive reanalysis of SPG4 HSP pedigrees
reveals large deletions as the sole cause. (Letter) Hum. Mutat. 28:
739-740, 2007.

4. Benson, K. F.; Horwitz, M.; Wolff, J.; Friend, K.; Thompson, E.;
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expansion in autosomal dominant familial spastic paraparesis: novel
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5. Brugman, F.; Wokke, J. H. J.; Scheffer, H.; Versteeg, M. H. A.;
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7. Burger, J.; Metzke, H.; Paternotte, C.; Schilling, F.; Hazan, J.;
Reis, A.: Autosomal dominant spastic paraplegia with anticipation
maps to a 4-cM interval on chromosome 2p21-p24 in a large German family. Hum.
Genet. 98: 371-375, 1996.

8. Charvin, D.; Cifuentes-Diaz, C.; Fonknechten, N.; Joshi, V.; Hazan,
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a loss of function of spastin, an abundant neuronal protein localized
in the nucleus. Hum. Molec. Genet. 12: 71-78, 2003.

9. Chinnery, P. F.; Keers, S. M.; Holden, M. J.; Ramesh, V.; Dalton,
A.: Infantile hereditary spastic paraparesis due to codominant mutations
in the spastin gene. Neurology 63: 710-712, 2004.

10. Ciccarelli, F. D.; Proukakis, C.; Patel, H.; Cross, H.; Azam,
S.; Patton, M. A.; Bork, P.; Crosby, A. H.: The identification of
a conserved domain in both spartin and spastin, mutated in hereditary
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11. Crippa, F.; Panzeri, C.; Martinuzzi, A.; Arnoldi, A.; Redaelli,
F.; Tonelli, A.; Baschirotto, C.; Vazza, G.; Mostacciuolo, M. L.;
Daga, A.; Orso, G.; Profice, P.; and 13 others: Eight novel mutations
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Neurol. 63: 750-755, 2006.

12. Depienne, C.; Fedirko, E.; Forlani, S.; Cazeneuve, C.; Ribai,
P.; Feki, I.; Tallaksen, C.; Nguyen, K.; Stankoff, B.; Ruberg, M.;
Stevanin, G.; Durr, A.; Brice, A.: Exon deletions of SPG4 are a frequent
cause of hereditary spastic paraplegia. (Letter) J. Med. Genet. 44:
281-284, 2007.

13. Errico, A.; Ballabio, A.; Rugarli, E. I.: Spastin, the protein
mutated in autosomal dominant hereditary spastic paraplegia, is involved
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14. Errico, A.; Claudiani, P.; D'Addio, M.; Rugarli, E. I.: Spastin
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2121-2132, 2004.

15. Evans, K.; Keller, C.; Pavur, K.; Glasgow, K.; Conn, B.; Lauring,
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spastin and atlastin, suggests a common pathway for axonal maintenance. Proc.
Nat. Acad. Sci. 103: 10666-10671, 2006.

16. Fonknechten, N.; Mavel, D.; Byrne, P.; Davoine, C.-S.; Cruaud,
C.; Bonsch, D.; Samson, D.; Coutinho, P.; Hutchinson, M.; McMonagle,
P.; Burgunder, J.-M.; Tartaglione, A.; and 10 others: Spectrum
of SPG4 mutations in autosomal dominant spastic paraplegia. Hum.
Molec. Genet. 9: 637-644, 2000. Note: Erratum: Hum. Molec. Genet.
14: 461 only, 2005.

17. Hazan, J.; Davoine, C. S.; Mavel, D.; Fonknechten, N.; Paternotte,
C.; Fizames, C.; Cruaud, C.; Samson, D.; Muselet, D.; Vega-Czarny,
N.; Brice, A.; Gyapay, G.; Heilig, R.; Fontaine, B.; Weissenbach,
J.: A fine integrated map of the SPG4 locus excludes an expanded
CAG repeat in chromosome 2p-linked autosomal dominant spastic paraplegia. Genomics 60:
309-319, 1999.

18. Hazan, J.; Fonknechten, N.; Mavel, D.; Paternotte, C.; Samson,
D.; Artiguenave, F.; Davoine, C.-S.; Cruaud, C.; Durr, A.; Wincker,
P.; Brottier, P.; Cattolico, L.; Barbe, V.; Burgunder, J.-M.; Prud'homme,
J.-F.; Brice, A.; Fontaine, B.; Heilig, R.; Weissenbach, J.: Spastin,
a new AAA protein, is altered in the most frequent form of autosomal
dominant spastic paraplegia. Nature Genet. 23: 296-303, 1999.

19. Ivanova, N.; Lofgren, A.; Tournev, I.; Rousev, R.; Andreeva, A.;
Jordanova, A.; Georgieva, V.; Deconinck, T.; Timmerman, V.; Kremensky,
I.; De Jonghe, P.; Mitev, V.: Spastin gene mutations in Bulgarian
patients with hereditary spastic paraplegia. Clin. Genet. 70: 490-495,
2006.

20. Iwanaga, H.; Tsujino, A.; Shirabe, S.; Eguchi, H.; Fukushima,
N.; Niikawa, N.; Yoshiura, K.; Eguchi, K.: Large deletion involving
the 5-prime-UTR in the spastin gene caused mild phenotype of autosomal
dominant hereditary spastic paraplegia. Am. J. Med. Genet. 133A:
13-17, 2005.

21. Ki, C.-S.; Lee, W. Y.; Han, D. H.; Sung, D. H.; Lee, K.-B.; Lee,
K.-A.; Cho, S. S.; Cho, S.; Hwang, H.; Sohn, K. M.; Choi, Y. J.; Kim,
J.-W.: A novel missense mutation (I344K) in the SPG4 gene in a Korean
family with autosomal-dominant hereditary spastic paraplegia. J.
Hum. Genet. 47: 473-477, 2002.

22. Lindsey, J. C.; Lusher, M. E.; McDermott, C. J.; White, K. D.;
Reid, E.; Rubinsztein, D. C.; Bashir, R.; Hazan, J.; Shaw, P. J.;
Bushby, K. M. D.: Mutation analysis of the spastin gene (SPG4) in
patients with hereditary spastic paraparesis. J. Med. Genet. 37:
759-765, 2000.

23. Mannan, A. U.; Boehm, J.; Sauter, S. M.; Rauber, A.; Byrne, P.
C.; Neesen, J.; Engel, W.: Spastin, the most commonly mutated protein
in hereditary spastic paraplegia interacts with reticulon 1 an endoplasmic
reticulum protein. Neurogenetics 7: 93-103, 2006.

24. McDermott, C. J.; Burness, C. E.; Kirby, J.; Cox, L. E.; Rao,
D. G.; Hewamadduma, C.; Sharrack, B.; Hadjivassiliou, M.; Chinnery,
P. F.; Dalton, A.; Shaw, P. J.: Clinical features of hereditary spastic
paraplegia due to spastin mutation. Neurology 67: 45-51, 2006. Note:
Erratum: Neurology 72: 1534 only, 2009.

25. McDermott, C. J.; Grierson, A. J.; Wood, J. D.; Bingley, M.; Wharton,
S. B.; Bushby, K. M. D.; Shaw, P. J.: Hereditary spastic paraparesis:
disrupted intracellular transport associated with spastin mutation. Ann.
Neurol. 54: 748-759, 2003.

26. McMonagle, P.; Byrne, P. C.; Fitzgerald, B.; Webb, S.; Parfrey,
N. A.; Hutchinson, M.: Phenotype of AD-HSP due to mutations in the
SPAST gene: comparison with AD-HSP without mutations. Neurology 55:
1794-1800, 2000.

27. Meijer, I. A.; Hand, C. K.; Cossette, P.; Figlewicz, D. A.; Rouleau,
G. A.: Spectrum of SPG4 mutations in a large collection of North
American families with hereditary spastic paraplegia. Arch. Neurol. 59:
281-286, 2002.

28. Mitne-Neto, M.; Kok, F.; Beetz, C.; Pessoa, A.; Bueno, C.; Graciani,
Z.; Martyn, M.; Monteiro, C. B. M.; Mitne, G.; Hubert, P.; Nygren,
A. O. H.; Valadares, M.; Cerqueira, A. M. P.; Starling, A.; Deufel,
T.; Zatz, M.: A multi-exonic SPG4 duplication underlies sex-dependent
penetrance of hereditary spastic paraplegia in a large Brazilian pedigree. Europ.
J. Hum. Genet. 15: 1276-1279, 2007.

29. Montenegro, G.; Rebelo, A. P.; Connell, J.; Allison, R.; Babalini,
C.; D'Aloia, M.; Montieri, P.; Schule, R.; Ishiura, H.; Price, J.;
Strickland, A.; Gonzalez, M. A.; and 13 others: Mutations in the
ER-shaping protein reticulon 2 cause the axon-degenerative disorder
hereditary spastic paraplegia type 12. J. Clin. Invest. 122: 538-544,
2012.

30. Nielsen, J. E.; Koefoed, P.; Abell, K.; Hasholt, L.; Eiberg, H.;
Fenger, K.; Niebuhr, E.; Sorensen, S. A.: CAG repeat expansion in
autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24. Hum.
Molec. Genet. 6: 1811-1816, 1997.

31. Orlacchio, A.; Kawarai, T.; Totaro, A.; Errico, A.; St George-Hyslop,
P. H.; Rugarli, E. I.; Bernardi, G.: Hereditary spastic paraplegia:
clinical genetic study of 15 families. Arch. Neurol. 61: 849-855,
2004.

32. Park, S.-Y.; Ki, C.-S.; Kim, H.-J.; Kim, J.-W.; Sung, D. H.; Kim,
B. J.; Lee, W. Y.: Mutation analysis of SPG4 and SPG3A genes and
its implication in molecular diagnosis of Korean patients with hereditary
spastic paraplegia. Arch. Neurol. 62: 1118-1121, 2005.

33. Reid, E.; Connell, J.; Edwards, T. L.; Duley, S.; Brown, S. E.;
Sanderson, C. M.: The hereditary spastic paraplegia protein spastin
interacts with the ESCRT-III complex-associated endosomal protein
CHMP1B. Hum. Molec. Genet. 14: 19-38, 2005.

34. Roll-Mecak, A.; Vale, R. D.: Structural basis of microtubule
severing by the hereditary spastic paraplegia protein spastin. Nature 451:
363-367, 2008.

35. Sanderson, C. M.; Connell, J. W.; Edwards, T. L.; Bright, N. A.;
Duley, S.; Thompson, A.; Luzio, J. P.; Reid, E.: Spastin and atlastin,
two proteins mutated in autosomal-dominant hereditary spastic paraplegia,
are binding partners. Hum. Molec. Genet. 15: 307-318, 2006.

36. Santorelli, F. M.; Patrono, C.; Fortini, D.; Tessa, A.; Comanducci,
G.; Bertini, E.; Pierallini, A.; Amabile, G. A.; Casali, C.: Intrafamilial
variability in hereditary spastic paraplegia associated with an SPG4
gene mutation. Neurology 55: 702-705, 2000.

37. Sauter, S.; Miterski, B.; Klimpe, S.; Bonsch, D.; Schols, L.;
Visbeck, A.; Papke, T.; Hopf, H. C.; Engel, W.; Deufel, T.; Epplen,
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patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum.
Mutat. 20: 127-132, 2002.

38. Schickel, J.; Beetz, C.; Frommel, C.; Heide, G.; Sasse, A.; Hemmerich,
P.; Deufel, T.: Unexpected pathogenic mechanism of a novel mutation
in the coding sequence of SPG4 (spastin). Neurology 66: 421-423,
2006.

39. Shoukier, M.; Neesen, J.; Sauter, S. M.; Argyriou, L.; Doerwald,
N.; Pantakani, D. V. K.; Mannan, A. U.: Expansion of mutation spectrum,
determination of mutation cluster regions and predictive structural
classification of SPAST mutations in hereditary spastic paraplegia. Europ.
J. Hum. Genet. 17: 187-194, 2009. Note: Erratum: Europ. J. Hum. Genet.
17: 401-402, 2009.

40. Starling, A.; Rocco, P.; Passos-Bueno, M. R.; Hazan, J.; Marie,
S. K.; Zatz, M.: Autosomal dominant (AD) pure spastic paraplegia
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pedigree. J. Med. Genet. 39: e77, 2002. Note: Electronic article.

41. Svenson, I. K.; Ashley-Koch, A. E.; Gaskell, P. C.; Riney, T.
J.; Cumming, W. J. K.; Kingston, H. M.; Hogan, E. L.; Boustany, R.-M.
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2001.

42. Svenson, I. K.; Ashley-Koch, A. E.; Pericak-Vance, M. A.; Marchuk,
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J. Hum. Genet. 69: 1407-1409, 2001.

43. Svenson, I. K.; Kloos, M. T.; Gaskell, P. C.; Nance, M. A.; Garbern,
J. Y.; Hisanaga, S.; Pericak-Vance, M. A.; Ashley-Koch, A. E.; Marchuk,
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to spastin gene mutations. Neurogenetics 5: 157-164, 2004.

44. Svenson, I. K.; Kloos, M. T.; Jacon, A.; Gallione, C.; Horton,
A. C.; Pericak-Vance, M. A.; Ehlers, M. D.; Marchuk, D. A.: Subcellular
localization of spastin: implications for the pathogenesis of hereditary
spastic paraplegia. Neurogenetics 6: 135-141, 2005.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/1/2012
Patricia A. Hartz - updated: 11/11/2009
Cassandra L. Kniffin - updated: 9/14/2009
Cassandra L. Kniffin - updated: 3/19/2008
Ada Hamosh - updated: 2/21/2008
Cassandra L. Kniffin - updated: 11/27/2007
Cassandra L. Kniffin - updated: 11/6/2007
George E. Tiller - updated: 10/31/2007
Cassandra L. Kniffin - updated: 8/20/2007
Cassandra L. Kniffin - updated: 7/24/2007
Cassandra L. Kniffin - updated: 6/8/2007
Cassandra L. Kniffin - updated: 4/27/2007
George E. Tiller - updated: 3/21/2007
Cassandra L. Kniffin - updated: 2/6/2007
Cassandra L. Kniffin - updated: 9/5/2006
Cassandra L. Kniffin - updated: 8/23/2006
Cassandra L. Kniffin - updated: 4/7/2006
Cassandra L. Kniffin - updated: 3/6/2006
Cassandra L. Kniffin - updated: 11/16/2005
Cassandra L. Kniffin - updated: 11/4/2005
Cassandra L. Kniffin - updated: 10/12/2005
Cassandra L. Kniffin - updated: 1/27/2005
Cassandra L. Kniffin - updated: 10/26/2004
George E. Tiller - updated: 10/26/2004
Cassandra L. Kniffin - updated: 7/27/2004
Cassandra L. Kniffin - updated: 2/6/2004
Victor A. McKusick - updated: 5/2/2003
Cassandra L. Kniffin - updated: 12/27/2002
Victor A. McKusick - updated: 10/2/2002
George E. Tiller - updated: 9/17/2002
Victor A. McKusick - updated: 8/20/2002
Victor A. McKusick - updated: 12/20/2001
Victor A. McKusick - updated: 6/13/2001
Majed J. Dasouki - updated: 1/30/2001
Victor A. McKusick - updated: 11/3/2000
Anne M. Stumpf - updated: 9/21/2000
George E. Tiller - updated: 4/14/2000

*FIELD* CD
Ada Hamosh: 11/2/1999

*FIELD* ED
carol: 09/24/2013
terry: 3/15/2013
carol: 3/2/2012
ckniffin: 3/1/2012
wwang: 3/2/2011
carol: 2/2/2010
wwang: 1/8/2010
mgross: 11/13/2009
terry: 11/11/2009
wwang: 9/14/2009
wwang: 4/10/2008
ckniffin: 3/19/2008
alopez: 3/19/2008
terry: 2/21/2008
terry: 12/17/2007
wwang: 12/4/2007
ckniffin: 11/27/2007
wwang: 11/13/2007
ckniffin: 11/6/2007
alopez: 11/2/2007
terry: 10/31/2007
wwang: 9/6/2007
ckniffin: 8/20/2007
wwang: 8/3/2007
ckniffin: 7/24/2007
wwang: 6/28/2007
ckniffin: 6/8/2007
wwang: 6/8/2007
ckniffin: 4/27/2007
wwang: 3/23/2007
terry: 3/21/2007
wwang: 2/8/2007
ckniffin: 2/6/2007
wwang: 9/7/2006
ckniffin: 9/5/2006
wwang: 8/29/2006
ckniffin: 8/23/2006
wwang: 4/11/2006
ckniffin: 4/7/2006
wwang: 3/13/2006
ckniffin: 3/6/2006
wwang: 11/22/2005
ckniffin: 11/16/2005
wwang: 11/14/2005
ckniffin: 11/4/2005
wwang: 10/26/2005
wwang: 10/24/2005
ckniffin: 10/12/2005
joanna: 5/18/2005
tkritzer: 2/1/2005
ckniffin: 1/27/2005
tkritzer: 11/1/2004
ckniffin: 10/26/2004
tkritzer: 10/26/2004
tkritzer: 7/28/2004
ckniffin: 7/27/2004
tkritzer: 2/17/2004
ckniffin: 2/6/2004
joanna: 10/31/2003
cwells: 5/5/2003
terry: 5/2/2003
carol: 1/6/2003
ckniffin: 12/27/2002
carol: 12/4/2002
tkritzer: 10/2/2002
cwells: 9/17/2002
tkritzer: 8/26/2002
tkritzer: 8/23/2002
terry: 8/20/2002
alopez: 1/11/2002
cwells: 1/10/2002
terry: 12/20/2001
alopez: 10/30/2001
cwells: 6/19/2001
cwells: 6/14/2001
terry: 6/13/2001
carol: 1/30/2001
mcapotos: 11/16/2000
mcapotos: 11/14/2000
terry: 11/3/2000
carol: 9/27/2000
alopez: 9/21/2000
alopez: 4/17/2000
terry: 4/14/2000
alopez: 11/2/1999

RBCC Red Blood Cell Collection

Full text data of SPAST