RBCC

Full text data of SOD1

SOD1 [Confidence: high (present in two of the MS resources)]
Superoxide dismutase [Cu-Zn]; 1.15.1.1 (Superoxide dismutase 1; hSod1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00218733
IPI00218733 Superoxide diSmutaSe 1, Soluble Destroys radicals which are normally produced within the cells and which are toxic to biological systems, 2 superoxide + 2 H+ = O2 + H2O2. soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight

UniProt P00441
ID SODC_HUMAN Reviewed; 154 AA.
AC P00441; A6NHJ0; D3DSE4; Q16669; Q16711; Q16838; Q16839; Q16840;
read moreAC Q6NR85;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 185.
DE RecName: Full=Superoxide dismutase [Cu-Zn];
DE EC=1.15.1.1;
DE AltName: Full=Superoxide dismutase 1;
DE Short=hSod1;
GN Name=SOD1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6577438; DOI=10.1073/pnas.80.18.5465;
RA Sherman L., Dafni N., Lieman-Hurwitz J., Groner Y.;
RT "Nucleotide sequence and expression of human chromosome 21-encoded
RT superoxide dismutase mRNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:5465-5469(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3160582;
RA Levanon D., Lieman-Hurwitz J., Dafni N., Wigderson M., Sherman L.,
RA Bernstein Y., Laver-Rudich Z., Danciger E., Stein O., Groner Y.;
RT "Architecture and anatomy of the chromosomal locus in human chromosome
RT 21 encoding the Cu/Zn superoxide dismutase.";
RL EMBO J. 4:77-84(1985).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3889846; DOI=10.1093/nar/13.6.2017;
RA Hallewell R.A., Masiarz F.R., Najarian R.C., Puma J.P., Quiroga M.R.,
RA Randolph A., Sanchez-Pescador R., Scandella C.J., Smith B.,
RA Steimer K.S., Mullenbach G.T.;
RT "Human Cu/Zn superoxide dismutase cDNA: isolation of clones
RT synthesising high levels of active or inactive enzyme from an
RT expression library.";
RL Nucleic Acids Res. 13:2017-2034(1985).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2853161;
RA Kajihara J., Enomoto M., Nishijima K., Yabuuchi M., Katoh K.;
RT "Comparison of properties between human recombinant and placental
RT copper-zinc SOD.";
RL J. Biochem. 104:851-854(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Xu Y., Hu X., Zhou Y., Peng X., Yuan J., Qiang B.;
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Lu X., Hui L.;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Staege M.S., Bergmann S., Heins S.;
RT "Direct sequencing and cloning of superoxide dismutase 1 from
RT peripheral blood.";
RL Submitted (NOV-2006) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [14]
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 [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [16]
RP PROTEIN SEQUENCE OF 2-154.
RX PubMed=6770891; DOI=10.1021/bi00552a005;
RA Jabusch J.R., Farb D.L., Kerschensteiner D.A., Deutsch H.F.;
RT "Some sulfhydryl properties and primary structure of human erythrocyte
RT superoxide dismutase.";
RL Biochemistry 19:2310-2316(1980).
RN [17]
RP PROTEIN SEQUENCE OF 2-154.
RX PubMed=7002610; DOI=10.1016/0014-5793(80)81044-1;
RA Barra D., Martini F., Bannister J.V., Schinina M.E., Rotilio G.,
RA Bannister W.H., Bossa F.;
RT "The complete amino acid sequence of human Cu/Zn superoxide
RT dismutase.";
RL FEBS Lett. 120:53-56(1980).
RN [18]
RP PROTEIN SEQUENCE OF 11-24 AND 81-116.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [19]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 25-56 AND 120-154, AND VARIANTS
RP ALS1 GLN-49; ARG-94; THR-113; THR-114; HIS-126 AND THR-150.
RX PubMed=8528216; DOI=10.1093/hmg/4.7.1239;
RA Enayat Z.E., Orrell R.W., Claus A., Ludolph A., Bachus R.,
RA Brockmueller J., Ray-Chaudhuri K., Radunovic A., Shaw C.,
RA Wilkinson J., King A., Swash M., Leigh P.N., de Belleroche J.,
RA Powell J.;
RT "Two novel mutations in the gene for copper zinc superoxide dismutase
RT in UK families with amyotrophic lateral sclerosis.";
RL Hum. Mol. Genet. 4:1239-1240(1995).
RN [20]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 120-154, AND VARIANT ALS1
RP THR-152.
RX PubMed=8682505; DOI=10.1007/s004390050157;
RA Kostrzewa M., Daamian M., Mueller U.;
RT "Superoxide dismutase 1: identification of a novel mutation in a case
RT of familial amyotrophic lateral sclerosis.";
RL Hum. Genet. 98:48-50(1996).
RN [21]
RP SUBUNIT, AND DISULFIDE BOND.
RX PubMed=15326189; DOI=10.1074/jbc.M406021200;
RA Arnesano F., Banci L., Bertini I., Martinelli M., Furukawa Y.,
RA O'Halloran T.V.;
RT "The unusually stable quaternary structure of human Cu,Zn-superoxide
RT dismutase 1 is controlled by both metal occupancy and disulfide
RT status.";
RL J. Biol. Chem. 279:47998-48003(2004).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-99, AND MASS
RP 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 [23]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-123, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [24]
RP SUBUNIT, AND DITRYPTOPHAN CROSS-LINK AT TRP-33.
RX PubMed=20600836; DOI=10.1016/j.freeradbiomed.2010.06.018;
RA Medinas D.B., Gozzo F.C., Santos L.F., Iglesias A.H., Augusto O.;
RT "A ditryptophan cross-link is responsible for the covalent
RT dimerization of human superoxide dismutase 1 during its bicarbonate-
RT dependent peroxidase activity.";
RL Free Radic. Biol. Med. 49:1046-1053(2010).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-99, 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [27]
RP PALMITOYLATION AT CYS-7, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP CYS-7.
RX PubMed=22496122; DOI=10.1161/CIRCRESAHA.112.269514;
RA Marin E.P., Derakhshan B., Lam T.T., Davalos A., Sessa W.C.;
RT "Endothelial cell palmitoylproteomic identifies novel lipid-modified
RT targets and potential substrates for protein acyl transferases.";
RL Circ. Res. 110:1336-1344(2012).
RN [28]
RP SUCCINYLATION AT LYS-123, DESUCCINYLATION BY SIRT5, AND MUTAGENESIS OF
RP LYS-123.
RX PubMed=24140062; DOI=10.1016/j.bbrc.2013.10.033;
RA Lin Z.F., Xu H.B., Wang J.Y., Lin Q., Ruan Z., Liu F.B., Jin W.,
RA Huang H.H., Chen X.;
RT "SIRT5 desuccinylates and activates SOD1 to eliminate ROS.";
RL Biochem. Biophys. Res. Commun. 0:0-0(2013).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RX PubMed=1463506; DOI=10.1073/pnas.89.13.6109;
RA Parge H.E., Hallewell R.A., Tainer J.A.;
RT "Atomic structures of wild-type and thermostable mutant recombinant
RT human Cu,Zn superoxide dismutase.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:6109-6113(1992).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF VARIANT ALS1 ARG-38.
RX PubMed=9541385;
RA Hart P.J., Liu H., Pellegrini M., Nersissian A.M., Gralla E.B.,
RA Valentine J.S., Eisenberg D.;
RT "Subunit asymmetry in the three-dimensional structure of a human
RT CuZnSOD mutant found in familial amyotrophic lateral sclerosis.";
RL Protein Sci. 7:545-555(1998).
RN [31]
RP STRUCTURE BY NMR.
RX PubMed=9718300; DOI=10.1021/bi9803473;
RA Banci L., Benedetto M., Bertini I., del Conte R., Piccioli M.,
RA Viezzoli M.S.;
RT "Solution structure of reduced monomeric Q133M2 copper, zinc
RT superoxide dismutase (SOD). Why is SOD a dimeric enzyme?";
RL Biochemistry 37:11780-11791(1998).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.02 ANGSTROMS) OF MUTANT
RP GLU-51/GLU-52/GLN-134, SUBUNIT, AND MUTAGENESIS OF 51-PHE-GLY-52 AND
RP GLU-134.
RX PubMed=10329151; DOI=10.1006/jmbi.1999.2681;
RA Ferraroni M., Rypniewski W., Wilson K.S., Viezzoli M.S., Banci L.,
RA Bertini I., Mangani S.;
RT "The crystal structure of the monomeric human SOD mutant
RT F50E/G51E/E133Q at atomic resolution. The enzyme mechanism
RT revisited.";
RL J. Mol. Biol. 288:413-426(1999).
RN [33]
RP STRUCTURE BY NMR OF MUTANT GLU51/GLU-52/GLN-134, AND SUBUNIT.
RX PubMed=12911296; DOI=10.1021/bi034324m;
RA Banci L., Bertini I., Cramaro F., Del Conte R., Viezzoli M.S.;
RT "Solution structure of Apo Cu,Zn superoxide dismutase: role of metal
RT ions in protein folding.";
RL Biochemistry 42:9543-9553(2003).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH COPPER AND ZINC
RP IONS, DISULFIDE BOND, SUBUNIT, AND CHARACTERIZATION OF VARIANTS ALS1
RP VAL-5 AND ARG-44.
RX PubMed=12963370; DOI=10.1016/S0022-2836(03)00889-1;
RA DiDonato M., Craig L., Huff M.E., Thayer M.M., Cardoso R.M.,
RA Kassmann C.J., Lo T.P., Bruns C.K., Powers E.T., Kelly J.W.,
RA Getzoff E.D., Tainer J.A.;
RT "ALS mutants of human superoxide dismutase form fibrous aggregates via
RT framework destabilization.";
RL J. Mol. Biol. 332:601-615(2003).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF VARIANTS ALS1 ASN-135 AND
RP ARG-47, AND FORMATION OF FIBRILLAR AGGREGATES.
RX PubMed=12754496; DOI=10.1038/nsb935;
RA Elam J.S., Taylor A.B., Strange R., Antonyuk S., Doucette P.A.,
RA Rodriguez J.A., Hasnain S.S., Hayward L.J., Valentine J.S.,
RA Yeates T.O., Hart P.J.;
RT "Amyloid-like filaments and water-filled nanotubes formed by SOD1
RT mutant proteins linked to familial ALS.";
RL Nat. Struct. Biol. 10:461-467(2003).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF VARIANTS ALS1 VAL-5 AND
RP THR-114, AND CHARACTERIZATION OF VARIANTS ALS1 VAL-5 AND THR-114.
RX PubMed=15056757; DOI=10.1073/pnas.0305143101;
RA Hough M.A., Grossmann J.G., Antonyuk S.V., Strange R.W.,
RA Doucette P.A., Rodriguez J.A., Whitson L.J., Hart P.J., Hayward L.J.,
RA Valentine J.S., Hasnain S.S.;
RT "Dimer destabilization in superoxide dismutase may result in disease-
RT causing properties: structures of motor neuron disease mutants.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:5976-5981(2004).
RN [37]
RP STRUCTURE BY NMR OF MUTANT ALA-7/SER-112, AND SUBUNIT.
RX PubMed=16291742; DOI=10.1074/jbc.M506497200;
RA Banci L., Bertini I., Cantini F., D'Amelio N., Gaggelli E.;
RT "Human SOD1 before harboring the catalytic metal: solution structure
RT of copper-depleted, disulfide-reduced form.";
RL J. Biol. Chem. 281:2333-2337(2006).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (1.07 ANGSTROMS) IN COMPLEXES WITH COPPER AND
RP ZINC IONS, DISULFIDE BOND, AND SUBUNIT.
RX PubMed=16406071; DOI=10.1016/j.jmb.2005.11.081;
RA Strange R.W., Antonyuk S.V., Hough M.A., Doucette P.A.,
RA Valentine J.S., Hasnain S.S.;
RT "Variable metallation of human superoxide dismutase: atomic resolution
RT crystal structures of Cu-Zn, Zn-Zn and as-isolated wild-type
RT enzymes.";
RL J. Mol. Biol. 356:1152-1162(2006).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF MUTANTS ALA-7/ALA-112 AND
RP ALA-7/ALA-58/ALA-112/ALA-147, AND MUTAGENESIS OF CYS-7; CYS-58;
RP CYS-112 AND CYS-147.
RX PubMed=17070542; DOI=10.1016/j.jmb.2006.09.048;
RA Hoernberg A., Logan D.T., Marklund S.L., Oliveberg M.;
RT "The coupling between disulphide status, metallation and dimer
RT interface strength in Cu/Zn superoxide dismutase.";
RL J. Mol. Biol. 365:333-342(2007).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF MUTANT SER-81/SER-84 IN
RP COMPLEX WITH COPPER IONS, SUBUNIT, MUTAGENESIS OF HIS-81 AND ASP-84,
RP AND COFACTOR.
RX PubMed=17888947; DOI=10.1016/j.jmb.2007.07.043;
RA Roberts B.R., Tainer J.A., Getzoff E.D., Malencik D.A., Anderson S.R.,
RA Bomben V.C., Meyers K.R., Karplus P.A., Beckman J.S.;
RT "Structural characterization of zinc-deficient human superoxide
RT dismutase and implications for ALS.";
RL J. Mol. Biol. 373:877-890(2007).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (1.15 ANGSTROMS) IN COMPLEX WITH COPPER AND ZINC
RP IONS, SUBUNIT, AND FORMATION OF FIBRILLAR AGGREGATES BY ZINC-DEPLETED
RP SOD1.
RX PubMed=17548825; DOI=10.1073/pnas.0703857104;
RA Strange R.W., Yong C.W., Smith W., Hasnain S.S.;
RT "Molecular dynamics using atomic-resolution structure reveal
RT structural fluctuations that may lead to polymerization of human Cu-Zn
RT superoxide dismutase.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:10040-10044(2007).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF VARIANT ALS1 ARG-86, AND
RP CHARACTERIZATION OF VARIANT ALS1 ARG-86.
RX PubMed=18378676; DOI=10.1074/jbc.M801522200;
RA Cao X., Antonyuk S.V., Seetharaman S.V., Whitson L.J., Taylor A.B.,
RA Holloway S.P., Strange R.W., Doucette P.A., Valentine J.S., Tiwari A.,
RA Hayward L.J., Padua S., Cohlberg J.A., Hasnain S.S., Hart P.J.;
RT "Structures of the G85R variant of SOD1 in familial amyotrophic
RT lateral sclerosis.";
RL J. Biol. Chem. 283:16169-16177(2008).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF VARIANT ALS1 ARG-86.
RG RIKEN structural genomics initiative (RSGI);
RT "Crystal structure of human Cu-Zn superoxide dismutase mutant G85R
RT (P21).";
RL Submitted (APR-2008) to the PDB data bank.
RN [44]
RP REVIEW ON VARIANTS.
RX PubMed=8592323;
RA de Belleroche J., Orrell R., King A.;
RT "Familial amyotrophic lateral sclerosis/motor neurone disease (FALS):
RT a review of current developments.";
RL J. Med. Genet. 32:841-847(1995).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 2-154 IN COMPLEX WITH ZINC.
RX PubMed=20727846; DOI=10.1016/j.abb.2010.08.014;
RA Seetharaman S.V., Taylor A.B., Holloway S., Hart P.J.;
RT "Structures of mouse SOD1 and human/mouse SOD1 chimeras.";
RL Arch. Biochem. Biophys. 503:183-190(2010).
RN [46]
RP VARIANTS ALS1.
RX PubMed=8446170; DOI=10.1038/362059a0;
RA Rosen D.R., Siddique T., Patterson D., Figlewicz D.A., Sapp P.,
RA Hentati A., Donaldson D., Goto J., O'Regan J.P., Deng H.-X.,
RA Rahmani Z., Krizus A., McKenna-Yasek D., Cayabyab A., Gaston S.M.,
RA Berger R., Tanzi R.E., Halperin J.J., Herzfeldt B., van den Bergh R.,
RA Hung W.-Y., Bird T., Deng G., Mulder D.W., Smyth C., Laing N.G.,
RA Soriano E., Pericak-Vance M.A., Haines J., Rouleau G.A., Gusella J.S.,
RA Horvitz H.R., Brown R.H. Jr.;
RT "Mutations in Cu/Zn superoxide dismutase gene are associated with
RT familial amyotrophic lateral sclerosis.";
RL Nature 362:59-62(1993).
RN [47]
RP ERRATUM.
RX PubMed=8332197;
RA Rosen D.R.;
RL Nature 364:362-362(1993).
RN [48]
RP VARIANTS ALS1.
RX PubMed=8351519; DOI=10.1126/science.8351519;
RA Deng H.-X., Hentati A., Tainer J.A., Iqbal Z., Cayabyab A.,
RA Hung W.-Y., Getzoff E.D., Hu P., Herzfeldt B., Roos R.P., Warner C.,
RA Deng G., Soriano E., Smyth C., Parge H.E., Ahmed A., Roses A.D.,
RA Hallewell R.A., Pericak-Vance M.A., Siddique T.;
RT "Amyotrophic lateral sclerosis and structural defects in Cu,Zn
RT superoxide dismutase.";
RL Science 261:1047-1051(1993).
RN [49]
RP VARIANT ALS1 THR-5.
RX PubMed=8179602; DOI=10.1006/bbrc.1994.1506;
RA Nakano R., Sato S., Inuzuka T., Sakimura K., Mishina M., Takahashi H.,
RA Ikuta F., Honma Y., Fujii J., Taniguchi N., Tsuji S.;
RT "A novel mutation in Cu/Zn superoxide dismutase gene in Japanese
RT familial amyotrophic lateral sclerosis.";
RL Biochem. Biophys. Res. Commun. 200:695-703(1994).
RN [50]
RP VARIANT ALS1 GLU-8.
RX PubMed=7980516; DOI=10.1006/bbrc.1994.2497;
RA Hirano M., Fujii J., Nagai Y., Sonobe M., Okamoto K., Araki H.,
RA Taniguchi N., Ueno S.;
RT "A new variant Cu/Zn superoxide dismutase (Val7-->Glu) deduced from
RT lymphocyte mRNA sequences from Japanese patients with familial
RT amyotrophic lateral sclerosis.";
RL Biochem. Biophys. Res. Commun. 204:572-577(1994).
RN [51]
RP VARIANT ALS1 LYS-22.
RX PubMed=8069312; DOI=10.1093/hmg/3.4.649;
RA Jones C.T., Swinger R.J., Brock D.J.H.;
RT "Identification of a novel SOD1 mutation in an apparently sporadic
RT amyotrophic lateral sclerosis patient and the detection of Ile113Thr
RT in three others.";
RL Hum. Mol. Genet. 3:649-650(1994).
RN [52]
RP VARIANTS ALS1 ASP-94 AND THR-113.
RX PubMed=7951252; DOI=10.1093/hmg/3.6.997;
RA Esteban J., Rosen D.R., Bowling A.C., Sapp P., McKenna-Yasek D.,
RA O'Regan J.P., Beal M.F., Horvitz H.R., Brown R.H. Jr.;
RT "Identification of two novel mutations and a new polymorphism in the
RT gene for Cu/Zn superoxide dismutase in patients with amyotrophic
RT lateral sclerosis.";
RL Hum. Mol. Genet. 3:997-998(1994).
RN [53]
RP VARIANT ALS1 GLY-116.
RX PubMed=7881433; DOI=10.1093/hmg/3.12.2261;
RA Kostrzewa M., Burck-Lehmann U., Mueller U.;
RT "Autosomal dominant amyotrophic lateral sclerosis: a novel mutation in
RT the Cu/Zn superoxide dismutase-1 gene.";
RL Hum. Mol. Genet. 3:2261-2262(1994).
RN [54]
RP VARIANT ALS1 ARG-47.
RX PubMed=7836951; DOI=10.1016/0022-510X(94)90097-3;
RA Aoki M., Ogasawara M., Matsubara Y., Narisawa K., Nakamura S.,
RA Itoyama Y., Abe K.;
RT "Familial amyotrophic lateral sclerosis (ALS) in Japan associated with
RT H46R mutation in Cu/Zn superoxide dismutase gene: a possible new
RT subtype of familial ALS.";
RL J. Neurol. Sci. 126:77-83(1994).
RN [55]
RP VARIANT ALS1 THR-114.
RX PubMed=7997024; DOI=10.1016/S0140-6736(94)92913-0;
RA Suthers G., Laing N., Wilton S., Dorosz S., Waddy H.;
RT "'Sporadic' motoneuron disease due to familial SOD1 mutation with low
RT penetrance.";
RL Lancet 344:1773-1773(1994).
RN [56]
RP VARIANT ALS1 ASN-102.
RX PubMed=7870076; DOI=10.1006/mcpr.1994.1046;
RA Jones C.T., Shaw P.J., Chari G., Brock D.J.;
RT "Identification of a novel exon 4 SOD1 mutation in a sporadic
RT amyotrophic lateral sclerosis patient.";
RL Mol. Cell. Probes 8:329-330(1994).
RN [57]
RP VARIANTS ALS1.
RX PubMed=7887412;
RA Pramatarova A., Figlewicz D.A., Krizus A., Han F.Y.,
RA Ceballos-Picot I., Nicole A., Dib M., Meininger V., Brown R.H. Jr.,
RA Rouleau G.A.;
RT "Identification of new mutations in the Cu/Zn superoxide dismutase
RT gene of patients with familial amyotrophic lateral sclerosis.";
RL Am. J. Hum. Genet. 56:592-596(1995).
RN [58]
RP VARIANT ALS1 ILE-149.
RX PubMed=7795609; DOI=10.1093/hmg/4.3.491;
RA Ikeda M., Abe K., Aoki M., Ogasawara M., Kameya T., Watanabe M.,
RA Shoji M., Hirai S., Itoyama Y.;
RT "A novel point mutation in the Cu/Zn superoxide dismutase gene in a
RT patient with familial amyotrophic lateral sclerosis.";
RL Hum. Mol. Genet. 4:491-492(1995).
RN [59]
RP VARIANT ALS1 GLY-102.
RX PubMed=7655468; DOI=10.1093/hmg/4.6.1101;
RA Yulug I.G., Katsanis N., de Belleroche J., Collinge J., Fisher E.M.C.;
RT "An improved protocol for the analysis of SOD1 gene mutations, and a
RT new mutation in exon 4.";
RL Hum. Mol. Genet. 4:1101-1104(1995).
RN [60]
RP VARIANT ALS1 ALA-91.
RX PubMed=7655469; DOI=10.1093/hmg/4.6.1105;
RA Sjaelander A., Beckman G., Deng H.-X., Iqbal Z., Tainer J.A.,
RA Siddique T.;
RT "The D90A mutation results in a polymorphism of Cu,Zn superoxide
RT dismutase that is prevalent in northern Sweden and Finland.";
RL Hum. Mol. Genet. 4:1105-1108(1995).
RN [61]
RP VARIANTS ALS1 MET-15 AND VAL-85.
RX PubMed=7655471; DOI=10.1093/hmg/4.6.1113;
RA Deng H.-X., Tainer J.A., Mitsumoto H., Ohnishi A., He X., Hung W.-Y.,
RA Zhao Y., Juneja T., Hentati A., Siddique T.;
RT "Two novel SOD1 mutations in patients with familial amyotrophic
RT lateral sclerosis.";
RL Hum. Mol. Genet. 4:1113-1116(1995).
RN [62]
RP VARIANT ALS1 ARG-94.
RX PubMed=7700376; DOI=10.1038/374504a0;
RA Orrell R., de Belleroche J., Marklund S., Bowe F., Hallewell R.;
RT "A novel SOD mutant and ALS.";
RL Nature 374:504-505(1995).
RN [63]
RP VARIANT ALS1 ALA-91.
RX PubMed=7647793; DOI=10.1038/ng0595-61;
RA Andersen P.M., Nilsson P., Ala-Hurula V., Keraenen M.-L.,
RA Tarvainen I., Haltia T., Nilsson L., Binzer M., Forsgren L.,
RA Marklund S.L.;
RT "Amyotrophic lateral sclerosis associated with homozygosity for an
RT Asp90Ala mutation in CuZn-superoxide dismutase.";
RL Nat. Genet. 10:61-66(1995).
RN [64]
RP VARIANT ALS1 PHE-105.
RX PubMed=7501156;
RA Ikeda M., Abe K., Aoki M., Sahara M., Watanabe M., Shoji M.,
RA St George-Hyslop P.H., Hirai S., Itoyama Y.;
RT "Variable clinical symptoms in familial amyotrophic lateral sclerosis
RT with a novel point mutation in the Cu/Zn superoxide dismutase gene.";
RL Neurology 45:2038-2042(1995).
RN [65]
RP VARIANTS ALS1 SER-145; THR-146 AND PHE-LEU-GLN-119 INS.
RX PubMed=7496169; DOI=10.1016/0960-8966(95)00007-A;
RA Sapp P.C., Rosen D.R., Hosler B.A., Esteban J., McKenna-Yasek D.,
RA O'Regan J.P., Horvitz H.R., Brown R.H. Jr.;
RT "Identification of three novel mutations in the gene for Cu/Zn
RT superoxide dismutase in patients with familial amyotrophic lateral
RT sclerosis.";
RL Neuromuscul. Disord. 5:353-357(1995).
RN [66]
RP VARIANTS ALS1 VAL-94; VAL-125 AND GLU-134 DEL.
RX PubMed=8938700; DOI=10.1016/0960-8966(96)00353-7;
RA Hosler B.A., Nicholson G.A., Sapp P.C., Chin W., Orrell R.W.,
RA de Belleroche J.S., Esteban J., Hayward L.J., Mckenna-Yasek D.,
RA Yeung L., Cherryson A.K., Dench J.E., Wilton S.D., Laing N.G.,
RA Horvitz R.H., Brown R.H. Jr.;
RT "Three novel mutations and two variants in the gene for Cu/Zn
RT superoxide dismutase in familial amyotrophic lateral sclerosis.";
RL Neuromuscul. Disord. 6:361-366(1996).
RN [67]
RP VARIANT ALS1 PHE-7.
RX PubMed=8907321; DOI=10.1016/0304-3940(96)12378-8;
RA Morita M., Aoki M., Abe K., Hasegawa T., Sakuma R., Onodera Y.,
RA Ichikawa N., Nishizawa M., Itoyama Y.;
RT "A novel two-base mutation in the Cu/Zn superoxide dismutase gene
RT associated with familial amyotrophic lateral sclerosis in Japan.";
RL Neurosci. Lett. 205:79-82(1996).
RN [68]
RP VARIANT ALS1 ASN-135.
RX PubMed=8990014;
RX DOI=10.1002/(SICI)1098-1004(1997)9:1<69::AID-HUMU14>3.3.CO;2-I;
RA Watanabe M., Aoki M., Abe K., Shoji M., Lizuka T., Ikeda Y., Hirai S.,
RA Kurokawa K., Kato T., Sasaki H., Itoyama Y.;
RT "A novel missense point mutation (S134N) of the Cu/Zn superoxide
RT dismutase gene in a patient with familial motor neuron disease.";
RL Hum. Mutat. 9:69-71(1997).
RN [69]
RP VARIANT ALS1 SER-17.
RX PubMed=9101297;
RX DOI=10.1002/(SICI)1098-1004(1997)9:4<356::AID-HUMU9>3.3.CO;2-3;
RA Kawamata J., Shimohama S., Takano S., Harada K., Ueda K., Kimura J.;
RT "Novel G16S (GGC-AGC) mutation in the SOD-1 gene in a patient with
RT apparently sporadic young-onset amyotrophic lateral sclerosis.";
RL Hum. Mutat. 9:356-358(1997).
RN [70]
RP VARIANT ALS1 SER-73.
RX PubMed=9455977; DOI=10.1016/S0022-510X(97)00181-0;
RA Orrell R.W., Marklund S.L., deBelleroche J.S.;
RT "Familial ALS is associated with mutations in all exons of SOD1: a
RT novel mutation in exon 3 (Gly72Ser).";
RL J. Neurol. Sci. 153:46-49(1997).
RN [71]
RP VARIANT ALS1 THR-114.
RX PubMed=10732812; DOI=10.1007/s100480050016;
RA Kikugawa K., Nakano R., Inuzuka T., Kokubo Y., Narita Y., Kuzuhara S.,
RA Yoshida S., Tsuji S.;
RT "A missense mutation in the SOD1 gene in patients with amyotrophic
RT lateral sclerosis from the Kii Peninsula and its vicinity, Japan.";
RL Neurogenetics 1:113-115(1997).
RN [72]
RP VARIANT ALS1 GLN-9.
RX PubMed=9131652; DOI=10.1016/S0960-8966(96)00419-1;
RA Bereznai B., Winkler A., Borasio G.D., Gasser T.;
RT "A novel SOD1 mutation in an Austrian family with amyotrophic lateral
RT sclerosis.";
RL Neuromuscul. Disord. 7:113-116(1997).
RN [73]
RP CHARACTERIZATION OF VARIANTS ALS1 VAL-5; ARG-38; ARG-47; GLN-49;
RP ARG-86 AND THR-114.
RX PubMed=10400992; DOI=10.1093/hmg/8.8.1451;
RA Ratovitski T., Corson L.B., Strain J., Wong P., Cleveland D.W.,
RA Culotta V.C., Borchelt D.R.;
RT "Variation in the biochemical/biophysical properties of mutant
RT superoxide dismutase 1 enzymes and the rate of disease progression in
RT familial amyotrophic lateral sclerosis kindreds.";
RL Hum. Mol. Genet. 8:1451-1460(1999).
RN [74]
RP VARIANT ALS1 ARG-13.
RX PubMed=10430435;
RA Penco S., Schenone A., Bordo D., Bolognesi M., Abbruzzese M.,
RA Bugiani O., Ajmar F., Garre C.;
RT "A SOD1 gene mutation in a patient with slowly progressing familial
RT ALS.";
RL Neurology 53:404-406(1999).
RN [75]
RP ERRATUM.
RA Penco S., Schenone A., Bordo D., Bolognesi M., Abbruzzese M.,
RA Bugiani O., Ajmar F., Garre C.;
RL Neurology 57:1146-1146(2001).
RN [76]
RP VARIANT ALS1 SER-127.
RX PubMed=11535232; DOI=10.1016/S0022-510X(01)00558-5;
RA Murakami T., Warita H., Hayashi T., Sato K., Manabe Y., Mizuno S.,
RA Yamane K., Abe K.;
RT "A novel SOD1 gene mutation in familial ALS with low penetrance in
RT females.";
RL J. Neurol. Sci. 189:45-47(2001).
RN [77]
RP VARIANT ALS1 CYS-46.
RX PubMed=11369193; DOI=10.1016/S0960-8966(00)00215-7;
RA Gellera C., Castellotti B., Riggio M.C., Silani V., Morandi L.,
RA Testa D., Casali C., Taroni F., Di Donato S., Zeviani M., Mariotti C.;
RT "Superoxide dismutase gene mutations in Italian patients with familial
RT and sporadic amyotrophic lateral sclerosis: identification of three
RT novel missense mutations.";
RL Neuromuscul. Disord. 11:404-410(2001).
RN [78]
RP VARIANT ALS1 ALA-81.
RX PubMed=12402272; DOI=10.1002/ana.10369;
RA Alexander M.D., Traynor B.J., Miller N., Corr B., Frost E.,
RA McQuaid S., Brett F.M., Green A., Hardiman O.;
RT "'True' sporadic ALS associated with a novel SOD-1 mutation.";
RL Ann. Neurol. 52:680-683(2002).
RN [79]
RP CHARACTERIZATION OF VARIANTS ALS1 ARG-38; ARG-47; ARG-86 AND ALA-94,
RP INTERACTION WITH RNF19A, AND UBIQUITINATION.
RX PubMed=12145308; DOI=10.1074/jbc.M206559200;
RA Niwa J., Ishigaki S., Hishikawa N., Yamamoto M., Doyu M., Murata S.,
RA Tanaka K., Taniguchi N., Sobue G.;
RT "Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated
RT neurotoxicity.";
RL J. Biol. Chem. 277:36793-36798(2002).
RN [80]
RP VARIANTS ALS1 VAL-9; CYS-21; LEU-23; ARG-49; ARG-55; ALA-88; THR-90;
RP MET-98; LEU-119; GLY-125 AND ARG-148.
RX PubMed=14506936;
RA Andersen P.M., Sims K.B., Xin W.W., Kiely R., O'Neill G., Ravits J.,
RA Pioro E., Harati Y., Brower R.D., Levine J.S., Heinicke H.U.,
RA Seltzer W., Boss M., Brown R.H. Jr.;
RT "Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in
RT amyotrophic lateral sclerosis: a decade of discoveries, defects and
RT disputes.";
RL Amyotroph. Lateral Scler. 4:62-73(2003).
RN [81]
RP CHARACTERIZATION OF VARIANTS ALS1 ARG-38; ARG-86 AND ARG-94,
RP MUTAGENESIS OF CYS-7; 51-PHE-GLY-52; CYS-58; HIS-81; ASP-84; CYS-112
RP AND CYS-147, AND MASS SPECTROMETRY.
RX PubMed=18552350; DOI=10.1074/jbc.M802083200;
RA Furukawa Y., Kaneko K., Yamanaka K., O'Halloran T.V., Nukina N.;
RT "Complete loss of post-translational modifications triggers fibrillar
RT aggregation of SOD1 in the familial form of amyotrophic lateral
RT sclerosis.";
RL J. Biol. Chem. 283:24167-24176(2008).
RN [82]
RP CHARACTERIZATION OF VARIANTS ALS1 ARG-55; ALA-91; ALA-94; ASP-94;
RP MET-98 AND PHE-145.
RX PubMed=18301754; DOI=10.1371/journal.pone.0001677;
RA Banci L., Bertini I., Boca M., Girotto S., Martinelli M.,
RA Valentine J.S., Vieru M.;
RT "SOD1 and amyotrophic lateral sclerosis: mutations and
RT oligomerization.";
RL PLoS ONE 3:E1677-E1677(2008).
RN [83]
RP CHARACTERIZATION OF VARIANTS ALS1 ARG-86 AND ALA-94, UBIQUITINATION BY
RP MARCH5, AND SUBCELLULAR LOCATION.
RX PubMed=19741096; DOI=10.1091/mbc.E09-02-0112;
RA Yonashiro R., Sugiura A., Miyachi M., Fukuda T., Matsushita N.,
RA Inatome R., Ogata Y., Suzuki T., Dohmae N., Yanagi S.;
RT "Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and
RT attenuates mutant SOD1-induced reactive oxygen species generation.";
RL Mol. Biol. Cell 20:4524-4530(2009).
RN [84]
RP VARIANT ALS1 PRO-68.
RX PubMed=21247266; DOI=10.3109/17482968.2011.551939;
RA del Grande A., Luigetti M., Conte A., Mancuso I., Lattante S.,
RA Marangi G., Stipa G., Zollino M., Sabatelli M.;
RT "A novel L67P SOD1 mutation in an Italian ALS patient.";
RL Amyotroph. Lateral Scler. 12:150-152(2011).
RN [85]
RP VARIANT ALS1 GLY-96.
RX PubMed=21220647; DOI=10.1001/archneurol.2010.352;
RA Chio A., Borghero G., Pugliatti M., Ticca A., Calvo A., Moglia C.,
RA Mutani R., Brunetti M., Ossola I., Marrosu M.G., Murru M.R.,
RA Floris G., Cannas A., Parish L.D., Cossu P., Abramzon Y.,
RA Johnson J.O., Nalls M.A., Arepalli S., Chong S., Hernandez D.G.,
RA Traynor B.J., Restagno G.;
RT "Large proportion of amyotrophic lateral sclerosis cases in Sardinia
RT due to a single founder mutation of the TARDBP gene.";
RL Arch. Neurol. 68:594-598(2011).
CC -!- FUNCTION: Destroys radicals which are normally produced within the
CC cells and which are toxic to biological systems.
CC -!- CATALYTIC ACTIVITY: 2 superoxide + 2 H(+) = O(2) + H(2)O(2).
CC -!- COFACTOR: Binds 1 copper ion per subunit.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- SUBUNIT: Homodimer; non-disulfide linked. Homodimerization may
CC take place via the ditryptophan cross-link at Trp-33. The
CC pathogenic variants ALS1 Arg-38, Arg-47, Arg-86 and Ala-94
CC interact with RNF19A, whereas wild-type protein does not. The
CC pathogenic variants ALS1 Arg-86 and Ala-94 interact with MARCH5,
CC whereas wild-type protein does not.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-990792, EBI-990792;
CC P26339:Chga (xeno); NbExp=5; IntAct=EBI-990792, EBI-990900;
CC P16014:Chgb (xeno); NbExp=6; IntAct=EBI-990792, EBI-990820;
CC Q8TCX1:DYNC2LI1; NbExp=3; IntAct=EBI-990792, EBI-8568003;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Predominantly
CC cytoplasmic; the pathogenic variants ALS1 Arg-86 and Ala-94
CC gradually aggregates and accumulates in mitochondria.
CC -!- PTM: Unlike wild-type protein, the pathogenic variants ALS1 Arg-
CC 38, Arg-47, Arg-86 and Ala-94 are polyubiquitinated by RNF19A
CC leading to their proteasomal degradation. The pathogenic variants
CC ALS1 Arg-86 and Ala-94 are ubiquitinated by MARCH5 leading to
CC their proteasomal degradation.
CC -!- PTM: The ditryptophan cross-link at Trp-33 is responsible for the
CC non-disulfide-linked homodimerization. Such modification might
CC only occur in extreme conditions and additional experimental
CC evidence is required.
CC -!- PTM: Palmitoylation helps nuclear targeting and decreases
CC catalytic activity.
CC -!- PTM: Succinylation, adjacent to copper catalytic site probably
CC inhibit activity. Desuccinylated by SIRT5, enhancing activity.
CC -!- DISEASE: Amyotrophic lateral sclerosis 1 (ALS1) [MIM:105400]: A
CC neurodegenerative disorder affecting upper motor neurons in the
CC brain and lower motor neurons in the brain stem and spinal cord,
CC resulting in fatal paralysis. Sensory abnormalities are absent.
CC The pathologic hallmarks of the disease include pallor of the
CC corticospinal tract due to loss of motor neurons, presence of
CC ubiquitin-positive inclusions within surviving motor neurons, and
CC deposition of pathologic aggregates. The etiology of amyotrophic
CC lateral sclerosis is likely to be multifactorial, involving both
CC genetic and environmental factors. The disease is inherited in 5-
CC 10% of the cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: The protein (both wild-type and ALS1 variants) has
CC a tendency to form fibrillar aggregates in the absence of the
CC intramolecular disulfide bond or of bound zinc ions. These
CC aggregates may have cytotoxic effects. Zinc binding promotes
CC dimerization and stabilizes the native form.
CC -!- SIMILARITY: Belongs to the Cu-Zn superoxide dismutase family.
CC -!- WEB RESOURCE: Name=Alsod; Note=ALS genetic mutations db;
CC URL="http://alsod.iop.kcl.ac.uk/Als/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SOD1";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/sod1/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Superoxide dismutase entry;
CC URL="http://en.wikipedia.org/wiki/Superoxide_dismutase";
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L44139; AAB05662.1; -; Genomic_DNA.
DR EMBL; L44135; AAB05662.1; JOINED; Genomic_DNA.
DR EMBL; L44136; AAB05662.1; JOINED; Genomic_DNA.
DR EMBL; L44137; AAB05662.1; JOINED; Genomic_DNA.
DR EMBL; L44139; AAB05661.1; -; Genomic_DNA.
DR EMBL; L44135; AAB05661.1; JOINED; Genomic_DNA.
DR EMBL; L44136; AAB05661.1; JOINED; Genomic_DNA.
DR EMBL; L44137; AAB05661.1; JOINED; Genomic_DNA.
DR EMBL; X02317; CAA26182.1; -; mRNA.
DR EMBL; X01780; CAA25915.1; -; Genomic_DNA.
DR EMBL; X01781; CAA25916.1; -; Genomic_DNA.
DR EMBL; X01782; CAA25917.1; ALT_SEQ; Genomic_DNA.
DR EMBL; X01783; CAA25918.1; -; Genomic_DNA.
DR EMBL; X01784; CAA25919.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AY049787; AAL15444.1; -; mRNA.
DR EMBL; AY450286; AAR21563.1; -; mRNA.
DR EMBL; EF151142; ABL96616.1; -; mRNA.
DR EMBL; AK312116; BAG35052.1; -; mRNA.
DR EMBL; CR450355; CAG29351.1; -; mRNA.
DR EMBL; CR541742; CAG46542.1; -; mRNA.
DR EMBL; BT006676; AAP35322.1; -; mRNA.
DR EMBL; AY835629; AAV80422.1; -; Genomic_DNA.
DR EMBL; AP000253; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471079; EAX09889.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09890.1; -; Genomic_DNA.
DR EMBL; BC001034; AAH01034.1; -; mRNA.
DR EMBL; L46374; AAB59626.1; -; Genomic_DNA.
DR EMBL; L46375; AAB59627.1; -; Genomic_DNA.
DR EMBL; L44746; AAC41773.1; ALT_SEQ; Genomic_DNA.
DR EMBL; X95228; CAA64520.1; -; Genomic_DNA.
DR PIR; A22703; DSHUCZ.
DR RefSeq; NP_000445.1; NM_000454.4.
DR UniGene; Hs.443914; -.
DR PDB; 1AZV; X-ray; 1.90 A; A/B=2-154.
DR PDB; 1BA9; NMR; -; A=2-154.
DR PDB; 1DSW; NMR; -; A=2-154.
DR PDB; 1FUN; X-ray; 2.85 A; A/B/C/D/E/F/G/H/I/J=2-153.
DR PDB; 1HL4; X-ray; 1.82 A; A/B/C/D=2-154.
DR PDB; 1HL5; X-ray; 1.80 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/S=2-154.
DR PDB; 1KMG; NMR; -; A=2-153.
DR PDB; 1L3N; NMR; -; A/B=2-153.
DR PDB; 1MFM; X-ray; 1.02 A; A=2-154.
DR PDB; 1N18; X-ray; 2.00 A; A/B/C/D/E/F/G/H/I/J=1-154.
DR PDB; 1N19; X-ray; 1.86 A; A/B=1-154.
DR PDB; 1OEZ; X-ray; 2.15 A; W/X/Y/Z=2-154.
DR PDB; 1OZT; X-ray; 2.50 A; G/H/I/J/K/L/M/N=2-154.
DR PDB; 1OZU; X-ray; 1.30 A; A/B=2-154.
DR PDB; 1P1V; X-ray; 1.40 A; A/B/C=2-153.
DR PDB; 1PTZ; X-ray; 1.80 A; A/B=2-154.
DR PDB; 1PU0; X-ray; 1.70 A; A/B/C/D/E/F/G/H/I/J=2-154.
DR PDB; 1RK7; NMR; -; A=2-154.
DR PDB; 1SOS; X-ray; 2.50 A; A/B/C/D/E/F/G/H/I/J=2-154.
DR PDB; 1SPD; X-ray; 2.40 A; A/B=2-154.
DR PDB; 1UXL; X-ray; 1.60 A; A/B/C/D/E/F/G/H/I/J=2-154.
DR PDB; 1UXM; X-ray; 1.90 A; A/B/C/D/E/F/G/H/I/J/K/L=2-154.
DR PDB; 2AF2; NMR; -; A/B=2-154.
DR PDB; 2C9S; X-ray; 1.24 A; A/F=2-154.
DR PDB; 2C9U; X-ray; 1.24 A; A/F=2-154.
DR PDB; 2C9V; X-ray; 1.07 A; A/F=2-154.
DR PDB; 2GBT; X-ray; 1.70 A; A/B/C/D=2-154.
DR PDB; 2GBU; X-ray; 2.00 A; A/B/C/D=2-154.
DR PDB; 2GBV; X-ray; 2.00 A; A/B/C/D/E/F/G/H/I/J=2-154.
DR PDB; 2LU5; NMR; -; A=2-154.
DR PDB; 2NNX; X-ray; 2.30 A; A/B/C/D=2-153.
DR PDB; 2R27; X-ray; 2.00 A; A/B=1-154.
DR PDB; 2V0A; X-ray; 1.15 A; A/F=2-154.
DR PDB; 2VR6; X-ray; 1.30 A; A/F=2-154.
DR PDB; 2VR7; X-ray; 1.58 A; A/F=2-154.
DR PDB; 2VR8; X-ray; 1.36 A; A/F=2-154.
DR PDB; 2WKO; X-ray; 1.97 A; A/F=2-154.
DR PDB; 2WYT; X-ray; 1.00 A; A/F=2-154.
DR PDB; 2WYZ; X-ray; 1.70 A; A/F=2-154.
DR PDB; 2WZ0; X-ray; 1.72 A; A/F=2-154.
DR PDB; 2WZ5; X-ray; 1.50 A; A/F=2-154.
DR PDB; 2WZ6; X-ray; 1.55 A; A/F=2-154.
DR PDB; 2XJK; X-ray; 1.45 A; A=2-154.
DR PDB; 2XJL; X-ray; 1.55 A; A=2-154.
DR PDB; 2ZKW; X-ray; 1.90 A; A/B=1-154.
DR PDB; 2ZKX; X-ray; 2.72 A; A/B/C/D=1-154.
DR PDB; 2ZKY; X-ray; 2.40 A; A/B/C/D/E/F/G/H/I/J=1-154.
DR PDB; 3CQP; X-ray; 1.95 A; A/B/C/D=2-154.
DR PDB; 3CQQ; X-ray; 1.90 A; A/B=2-154.
DR PDB; 3ECU; X-ray; 1.90 A; A/B/C/D=2-154.
DR PDB; 3ECV; X-ray; 1.90 A; A/B/C/D=2-154.
DR PDB; 3ECW; X-ray; 2.15 A; A/B/C/D=2-154.
DR PDB; 3GQF; X-ray; 2.20 A; A/B/C/D/E/F=2-154.
DR PDB; 3GTV; X-ray; 2.20 A; A/B/C/D/E/F/G/H/I/J/K/L=2-81.
DR PDB; 3GZO; X-ray; 2.10 A; A/B/C/D/E/F/G/H/I/J=2-154.
DR PDB; 3GZP; X-ray; 3.10 A; A/B/C/D=2-154.
DR PDB; 3GZQ; X-ray; 1.40 A; A/B=2-154.
DR PDB; 3H2P; X-ray; 1.55 A; A/B=2-154.
DR PDB; 3H2Q; X-ray; 1.85 A; A/B/C/D=2-154.
DR PDB; 3HFF; X-ray; 2.20 A; A=2-154.
DR PDB; 3K91; X-ray; 1.75 A; A/B=2-154.
DR PDB; 3KH3; X-ray; 3.50 A; A/B/C/D/E/F/G/H/I/J/K/L=2-154.
DR PDB; 3KH4; X-ray; 3.50 A; A/B/C/D/E/F=2-154.
DR PDB; 3LTV; X-ray; 2.45 A; A/B/C/D/E/F=4-154.
DR PDB; 3QQD; X-ray; 1.65 A; A/B=2-154.
DR PDB; 3RE0; X-ray; 2.28 A; A/B/C/D=2-154.
DR PDB; 3T5W; X-ray; 1.80 A; A/B/D/E/F/G/H/I/J/K/L/M=2-154.
DR PDB; 4A7G; X-ray; 1.24 A; A/F=2-154.
DR PDB; 4A7Q; X-ray; 1.22 A; A/F=2-154.
DR PDB; 4A7S; X-ray; 1.06 A; A/F=2-154.
DR PDB; 4A7T; X-ray; 1.45 A; A/F=2-154.
DR PDB; 4A7U; X-ray; 0.98 A; A/F=2-154.
DR PDB; 4A7V; X-ray; 1.00 A; A/F=2-154.
DR PDB; 4B3E; X-ray; 2.15 A; A/B/C/D/E/F/G/H/I/J=1-154.
DR PDB; 4BCY; X-ray; 1.27 A; A=2-154.
DR PDB; 4BCZ; X-ray; 1.93 A; A/B=2-154.
DR PDB; 4BD4; X-ray; 2.78 A; A/B/C/D/E/F/G/H/I=2-154.
DR PDB; 4FF9; X-ray; 2.50 A; A/B=2-154.
DR PDB; 4SOD; Model; -; A=1-154.
DR PDBsum; 1AZV; -.
DR PDBsum; 1BA9; -.
DR PDBsum; 1DSW; -.
DR PDBsum; 1FUN; -.
DR PDBsum; 1HL4; -.
DR PDBsum; 1HL5; -.
DR PDBsum; 1KMG; -.
DR PDBsum; 1L3N; -.
DR PDBsum; 1MFM; -.
DR PDBsum; 1N18; -.
DR PDBsum; 1N19; -.
DR PDBsum; 1OEZ; -.
DR PDBsum; 1OZT; -.
DR PDBsum; 1OZU; -.
DR PDBsum; 1P1V; -.
DR PDBsum; 1PTZ; -.
DR PDBsum; 1PU0; -.
DR PDBsum; 1RK7; -.
DR PDBsum; 1SOS; -.
DR PDBsum; 1SPD; -.
DR PDBsum; 1UXL; -.
DR PDBsum; 1UXM; -.
DR PDBsum; 2AF2; -.
DR PDBsum; 2C9S; -.
DR PDBsum; 2C9U; -.
DR PDBsum; 2C9V; -.
DR PDBsum; 2GBT; -.
DR PDBsum; 2GBU; -.
DR PDBsum; 2GBV; -.
DR PDBsum; 2LU5; -.
DR PDBsum; 2NNX; -.
DR PDBsum; 2R27; -.
DR PDBsum; 2V0A; -.
DR PDBsum; 2VR6; -.
DR PDBsum; 2VR7; -.
DR PDBsum; 2VR8; -.
DR PDBsum; 2WKO; -.
DR PDBsum; 2WYT; -.
DR PDBsum; 2WYZ; -.
DR PDBsum; 2WZ0; -.
DR PDBsum; 2WZ5; -.
DR PDBsum; 2WZ6; -.
DR PDBsum; 2XJK; -.
DR PDBsum; 2XJL; -.
DR PDBsum; 2ZKW; -.
DR PDBsum; 2ZKX; -.
DR PDBsum; 2ZKY; -.
DR PDBsum; 3CQP; -.
DR PDBsum; 3CQQ; -.
DR PDBsum; 3ECU; -.
DR PDBsum; 3ECV; -.
DR PDBsum; 3ECW; -.
DR PDBsum; 3GQF; -.
DR PDBsum; 3GTV; -.
DR PDBsum; 3GZO; -.
DR PDBsum; 3GZP; -.
DR PDBsum; 3GZQ; -.
DR PDBsum; 3H2P; -.
DR PDBsum; 3H2Q; -.
DR PDBsum; 3HFF; -.
DR PDBsum; 3K91; -.
DR PDBsum; 3KH3; -.
DR PDBsum; 3KH4; -.
DR PDBsum; 3LTV; -.
DR PDBsum; 3QQD; -.
DR PDBsum; 3RE0; -.
DR PDBsum; 3T5W; -.
DR PDBsum; 4A7G; -.
DR PDBsum; 4A7Q; -.
DR PDBsum; 4A7S; -.
DR PDBsum; 4A7T; -.
DR PDBsum; 4A7U; -.
DR PDBsum; 4A7V; -.
DR PDBsum; 4B3E; -.
DR PDBsum; 4BCY; -.
DR PDBsum; 4BCZ; -.
DR PDBsum; 4BD4; -.
DR PDBsum; 4FF9; -.
DR PDBsum; 4SOD; -.
DR DisProt; DP00652; -.
DR ProteinModelPortal; P00441; -.
DR SMR; P00441; 2-154.
DR DIP; DIP-44941N; -.
DR IntAct; P00441; 12.
DR MINT; MINT-204523; -.
DR STRING; 9606.ENSP00000270142; -.
DR BindingDB; P00441; -.
DR ChEMBL; CHEMBL2354; -.
DR PhosphoSite; P00441; -.
DR DMDM; 134611; -.
DR DOSAC-COBS-2DPAGE; P00441; -.
DR OGP; P00441; -.
DR REPRODUCTION-2DPAGE; IPI00783680; -.
DR SWISS-2DPAGE; P00441; -.
DR UCD-2DPAGE; P00441; -.
DR PaxDb; P00441; -.
DR PeptideAtlas; P00441; -.
DR PRIDE; P00441; -.
DR DNASU; 6647; -.
DR Ensembl; ENST00000270142; ENSP00000270142; ENSG00000142168.
DR GeneID; 6647; -.
DR KEGG; hsa:6647; -.
DR UCSC; uc002ypa.3; human.
DR CTD; 6647; -.
DR GeneCards; GC21P033031; -.
DR HGNC; HGNC:11179; SOD1.
DR HPA; CAB008670; -.
DR HPA; HPA001401; -.
DR MIM; 105400; phenotype.
DR MIM; 147450; gene.
DR neXtProt; NX_P00441; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA334; -.
DR eggNOG; COG2032; -.
DR HOVERGEN; HBG000062; -.
DR InParanoid; P00441; -.
DR KO; K04565; -.
DR OMA; KVVQQTS; -.
DR OrthoDB; EOG776SR4; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; SOD1; human.
DR EvolutionaryTrace; P00441; -.
DR GeneWiki; SOD1; -.
DR GenomeRNAi; 6647; -.
DR NextBio; 25903; -.
DR PRO; PR:P00441; -.
DR ArrayExpress; P00441; -.
DR Bgee; P00441; -.
DR CleanEx; HS_SOD1; -.
DR Genevestigator; P00441; -.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0032839; C:dendrite cytoplasm; IDA:UniProtKB.
DR GO; GO:0031012; C:extracellular matrix; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; NAS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; NAS:UniProtKB.
DR GO; GO:0030346; F:protein phosphatase 2B binding; IDA:UniProtKB.
DR GO; GO:0048365; F:Rac GTPase binding; IDA:UniProtKB.
DR GO; GO:0004784; F:superoxide dismutase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0000187; P:activation of MAPK activity; ISS:UniProtKB.
DR GO; GO:0008089; P:anterograde axon cargo transport; ISS:BHF-UCL.
DR GO; GO:0006309; P:apoptotic DNA fragmentation; ISS:UniProtKB.
DR GO; GO:0060088; P:auditory receptor cell stereocilium organization; ISS:UniProtKB.
DR GO; GO:0007569; P:cell aging; IMP:UniProtKB.
DR GO; GO:0006879; P:cellular iron ion homeostasis; ISS:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR GO; GO:0007566; P:embryo implantation; ISS:UniProtKB.
DR GO; GO:0006749; P:glutathione metabolic process; ISS:UniProtKB.
DR GO; GO:0060047; P:heart contraction; IDA:UniProtKB.
DR GO; GO:0050665; P:hydrogen peroxide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB.
DR GO; GO:0046716; P:muscle cell cellular homeostasis; ISS:UniProtKB.
DR GO; GO:0002262; P:myeloid cell homeostasis; ISS:UniProtKB.
DR GO; GO:0045541; P:negative regulation of cholesterol biosynthetic process; IDA:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0060052; P:neurofilament cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0001541; P:ovarian follicle development; ISS:UniProtKB.
DR GO; GO:0032287; P:peripheral nervous system myelin maintenance; ISS:UniProtKB.
DR GO; GO:0001890; P:placenta development; NAS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IC:UniProtKB.
DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:UniProtKB.
DR GO; GO:1902177; P:positive regulation of intrinsic apoptotic signaling pathway in response to oxidative stress; IMP:BHF-UCL.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; IDA:UniProtKB.
DR GO; GO:0008217; P:regulation of blood pressure; ISS:UniProtKB.
DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IMP:UniProtKB.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISS:UniProtKB.
DR GO; GO:0046620; P:regulation of organ growth; NAS:UniProtKB.
DR GO; GO:0032314; P:regulation of Rac GTPase activity; IDA:UniProtKB.
DR GO; GO:0033081; P:regulation of T cell differentiation in thymus; NAS:UniProtKB.
DR GO; GO:0060087; P:relaxation of vascular smooth muscle; ISS:UniProtKB.
DR GO; GO:0019430; P:removal of superoxide radicals; ISS:UniProtKB.
DR GO; GO:0001975; P:response to amphetamine; IEA:Ensembl.
DR GO; GO:0048678; P:response to axon injury; ISS:UniProtKB.
DR GO; GO:0046688; P:response to copper ion; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; ISS:UniProtKB.
DR GO; GO:0045471; P:response to ethanol; ISS:UniProtKB.
DR GO; GO:0009408; P:response to heat; ISS:UniProtKB.
DR GO; GO:0042542; P:response to hydrogen peroxide; ISS:UniProtKB.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0001895; P:retina homeostasis; ISS:UniProtKB.
DR GO; GO:0008090; P:retrograde axon cargo transport; ISS:BHF-UCL.
DR GO; GO:0007605; P:sensory perception of sound; ISS:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0042554; P:superoxide anion generation; IEA:Ensembl.
DR GO; GO:0048538; P:thymus development; NAS:UniProtKB.
DR Gene3D; 2.60.40.200; -; 1.
DR InterPro; IPR024134; SOD_Cu/Zn_/chaperone.
DR InterPro; IPR018152; SOD_Cu/Zn_BS.
DR InterPro; IPR001424; SOD_Cu_Zn_dom.
DR PANTHER; PTHR10003; PTHR10003; 1.
DR Pfam; PF00080; Sod_Cu; 1.
DR PRINTS; PR00068; CUZNDISMTASE.
DR SUPFAM; SSF49329; SSF49329; 1.
DR PROSITE; PS00087; SOD_CU_ZN_1; 1.
DR PROSITE; PS00332; SOD_CU_ZN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis; Antioxidant;
KW Complete proteome; Copper; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Lipoprotein; Metal-binding;
KW Neurodegeneration; Nucleus; Oxidoreductase; Palmitate; Phosphoprotein;
KW Reference proteome; Ubl conjugation; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 154 Superoxide dismutase [Cu-Zn].
FT /FTId=PRO_0000164057.
FT METAL 47 47 Copper; catalytic.
FT METAL 49 49 Copper; catalytic.
FT METAL 64 64 Copper; catalytic.
FT METAL 64 64 Zinc; via pros nitrogen.
FT METAL 72 72 Zinc; via pros nitrogen.
FT METAL 81 81 Zinc; via pros nitrogen.
FT METAL 84 84 Zinc; structural.
FT METAL 121 121 Copper; catalytic.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 99 99 Phosphoserine.
FT MOD_RES 123 123 N6-acetyllysine; alternate.
FT MOD_RES 123 123 N6-succinyllysine; alternate.
FT MOD_RES 137 137 N6-acetyllysine (By similarity).
FT LIPID 7 7 S-palmitoyl cysteine.
FT DISULFID 58 147
FT CROSSLNK 33 33 1-(tryptophan-3-yl)-tryptophan (Trp-Trp)
FT (interchain with W-33).
FT VARIANT 5 5 A -> S (in ALS1).
FT /FTId=VAR_013518.
FT VARIANT 5 5 A -> T (in ALS1).
FT /FTId=VAR_007130.
FT VARIANT 5 5 A -> V (in ALS1; severe form; reduces
FT structural stability and enzyme activity;
FT increases tendency to form fibrillar
FT aggregates).
FT /FTId=VAR_007131.
FT VARIANT 7 7 C -> F (in ALS1).
FT /FTId=VAR_008717.
FT VARIANT 8 8 V -> E (in ALS1).
FT /FTId=VAR_007132.
FT VARIANT 9 9 L -> Q (in ALS1).
FT /FTId=VAR_013519.
FT VARIANT 9 9 L -> V (in ALS1).
FT /FTId=VAR_013520.
FT VARIANT 13 13 G -> R (in ALS1).
FT /FTId=VAR_013521.
FT VARIANT 15 15 V -> G (in ALS1).
FT /FTId=VAR_013522.
FT VARIANT 15 15 V -> M (in ALS1).
FT /FTId=VAR_007133.
FT VARIANT 17 17 G -> S (in ALS1; sporadic young onset).
FT /FTId=VAR_007134.
FT VARIANT 21 21 F -> C (in ALS1).
FT /FTId=VAR_045876.
FT VARIANT 22 22 E -> G (in ALS1).
FT /FTId=VAR_013523.
FT VARIANT 22 22 E -> K (in ALS1).
FT /FTId=VAR_007135.
FT VARIANT 23 23 Q -> L (in ALS1).
FT /FTId=VAR_045877.
FT VARIANT 38 38 G -> R (in ALS1; mild form; ubiquitinated
FT by RNF19A. Ubiquitinated by MARCH5;
FT leading to the degradation of
FT mitochondrial SOD1).
FT /FTId=VAR_007136.
FT VARIANT 39 39 L -> R (in ALS1).
FT /FTId=VAR_013524.
FT VARIANT 39 39 L -> V (in ALS1).
FT /FTId=VAR_007137.
FT VARIANT 42 42 G -> D (in ALS1).
FT /FTId=VAR_007139.
FT VARIANT 42 42 G -> S (in ALS1).
FT /FTId=VAR_007138.
FT VARIANT 44 44 H -> R (in ALS1; reduces structural
FT stability and enzyme activity; increases
FT tendency to form fibrillar aggregates).
FT /FTId=VAR_007140.
FT VARIANT 46 46 F -> C (in ALS1; slow progression).
FT /FTId=VAR_013525.
FT VARIANT 47 47 H -> R (in ALS1; "benign" form; 80% of
FT wild-type activity; ubiquitinated by
FT RNF19A).
FT /FTId=VAR_007141.
FT VARIANT 49 49 H -> Q (in ALS1).
FT /FTId=VAR_007142.
FT VARIANT 49 49 H -> R (in ALS1).
FT /FTId=VAR_045878.
FT VARIANT 50 50 E -> K (in ALS1).
FT /FTId=VAR_013526.
FT VARIANT 55 55 T -> R (in ALS1; reduces tendency to form
FT fibrillar aggregates).
FT /FTId=VAR_045879.
FT VARIANT 66 66 N -> S (in ALS1).
FT /FTId=VAR_013527.
FT VARIANT 68 68 L -> P (in ALS1).
FT /FTId=VAR_065560.
FT VARIANT 68 68 L -> R (in ALS1).
FT /FTId=VAR_013528.
FT VARIANT 73 73 G -> S (in ALS1).
FT /FTId=VAR_008718.
FT VARIANT 77 77 D -> Y (in ALS1).
FT /FTId=VAR_013529.
FT VARIANT 81 81 H -> A (in ALS1; sporadic form;
FT interferes with zinc binding; requires 2
FT nucleotide substitutions).
FT /FTId=VAR_016874.
FT VARIANT 85 85 L -> F (in ALS1).
FT /FTId=VAR_013530.
FT VARIANT 85 85 L -> V (in ALS1).
FT /FTId=VAR_007143.
FT VARIANT 86 86 G -> R (in ALS1; ubiquitinated by RNF19A;
FT interferes with zinc-binding.
FT Ubiquitinated by MARCH5; leading to the
FT degradation of mitochondrial SOD1).
FT /FTId=VAR_007144.
FT VARIANT 87 87 N -> S (in ALS1; dbSNP:rs11556620).
FT /FTId=VAR_013531.
FT VARIANT 88 88 V -> A (in ALS1).
FT /FTId=VAR_045880.
FT VARIANT 90 90 A -> T (in ALS1).
FT /FTId=VAR_045881.
FT VARIANT 90 90 A -> V (in ALS1).
FT /FTId=VAR_013532.
FT VARIANT 91 91 D -> A (in ALS1; does not seem to be
FT linked with a decrease in activity;
FT dbSNP:rs80265967).
FT /FTId=VAR_007145.
FT VARIANT 91 91 D -> V (in ALS1).
FT /FTId=VAR_013533.
FT VARIANT 94 94 G -> A (in ALS1; increases tendency to
FT form fibrillar aggregates; ubiquitinated
FT by RNF19A).
FT /FTId=VAR_007146.
FT VARIANT 94 94 G -> C (in ALS1).
FT /FTId=VAR_007147.
FT VARIANT 94 94 G -> D (in ALS1).
FT /FTId=VAR_007148.
FT VARIANT 94 94 G -> R (in ALS1; 30% of wild-type
FT activity).
FT /FTId=VAR_007149.
FT VARIANT 94 94 G -> V (in ALS1).
FT /FTId=VAR_008719.
FT VARIANT 96 96 A -> G (in ALS1).
FT /FTId=VAR_065194.
FT VARIANT 98 98 V -> M (in ALS1; increases tendency to
FT form fibrillar aggregates).
FT /FTId=VAR_045882.
FT VARIANT 101 101 E -> G (in ALS1).
FT /FTId=VAR_007150.
FT VARIANT 101 101 E -> K (in ALS1).
FT /FTId=VAR_013534.
FT VARIANT 102 102 D -> G (in ALS1).
FT /FTId=VAR_007151.
FT VARIANT 102 102 D -> N (in ALS1).
FT /FTId=VAR_007152.
FT VARIANT 105 105 I -> F (in ALS1).
FT /FTId=VAR_008720.
FT VARIANT 106 106 S -> L (in ALS1).
FT /FTId=VAR_013535.
FT VARIANT 107 107 L -> V (in ALS1).
FT /FTId=VAR_007153.
FT VARIANT 109 109 G -> V (in ALS1).
FT /FTId=VAR_013536.
FT VARIANT 113 113 I -> M (in ALS1).
FT /FTId=VAR_013537.
FT VARIANT 113 113 I -> T (in ALS1).
FT /FTId=VAR_007154.
FT VARIANT 114 114 I -> T (in ALS1; destabilizes dimeric
FT protein structure and increases tendency
FT to form fibrillar aggregates).
FT /FTId=VAR_007155.
FT VARIANT 115 115 G -> A (in ALS1).
FT /FTId=VAR_013538.
FT VARIANT 116 116 R -> G (in ALS1).
FT /FTId=VAR_007156.
FT VARIANT 119 119 V -> L (in ALS1).
FT /FTId=VAR_045883.
FT VARIANT 119 119 V -> VFLQ (in ALS1).
FT /FTId=VAR_008721.
FT VARIANT 125 125 D -> G (in ALS1).
FT /FTId=VAR_045884.
FT VARIANT 125 125 D -> V (in ALS1).
FT /FTId=VAR_008722.
FT VARIANT 126 126 D -> H (in ALS1).
FT /FTId=VAR_007157.
FT VARIANT 127 127 L -> S (in ALS1).
FT /FTId=VAR_013539.
FT VARIANT 134 134 Missing (in ALS).
FT /FTId=VAR_008723.
FT VARIANT 135 135 S -> N (in ALS1; reduced metal binding;
FT increases tendency to form fibrillar
FT aggregates).
FT /FTId=VAR_007158.
FT VARIANT 140 140 N -> K (in ALS1).
FT /FTId=VAR_007159.
FT VARIANT 145 145 L -> F (in ALS1).
FT /FTId=VAR_007160.
FT VARIANT 145 145 L -> S (in ALS1).
FT /FTId=VAR_008724.
FT VARIANT 146 146 A -> T (in ALS1).
FT /FTId=VAR_008725.
FT VARIANT 147 147 C -> R (in ALS1).
FT /FTId=VAR_013540.
FT VARIANT 148 148 G -> R (in ALS1).
FT /FTId=VAR_045885.
FT VARIANT 149 149 V -> G (in ALS1).
FT /FTId=VAR_007161.
FT VARIANT 149 149 V -> I (in ALS1).
FT /FTId=VAR_007162.
FT VARIANT 150 150 I -> T (in ALS1).
FT /FTId=VAR_007163.
FT VARIANT 152 152 I -> T (in ALS1; seems to affect
FT formation of homodimer).
FT /FTId=VAR_007164.
FT MUTAGEN 7 7 C->S: Enhances formation of fibrillar
FT aggregates in the absence of bound zinc;
FT when associated with S-58; S-112 and S-
FT 147.
FT MUTAGEN 7 7 C->S: No palmitoylation, reduced nuclear
FT targeting.
FT MUTAGEN 51 52 FG->EE: Abolishes dimerization; when
FT associated with Q-134.
FT MUTAGEN 58 58 C->S: Enhances formation of fibrillar
FT aggregates in the absence of bound zinc;
FT when associated with S-7; S-112 and S-
FT 147.
FT MUTAGEN 81 81 H->A: Loss of zinc binding and enhanced
FT tendency to form aggregates; when
FT associated with A-84.
FT MUTAGEN 81 81 H->S: Destabilization of dimer and loss
FT of zinc binding; when associated with S-
FT 84.
FT MUTAGEN 84 84 D->A: Loss of zinc binding and enhanced
FT tendency to form aggregates; when
FT associated with A-81.
FT MUTAGEN 84 84 D->S: Destabilization of dimer and loss
FT of zinc binding; when associated with S-
FT 81.
FT MUTAGEN 112 112 C->S: Enhances formation of fibrillar
FT aggregates in the absence of bound zinc;
FT when associated with S-7; S-58 and S-147.
FT MUTAGEN 123 123 K->A: Deacreased succinylation.
FT MUTAGEN 123 123 K->E: Mimicks constitutive succinylation
FT state; decreased activity.
FT MUTAGEN 134 134 E->Q: Abolishes dimerization; when
FT associated with E-50 and E-51.
FT MUTAGEN 147 147 C->S: Enhances formation of fibrillar
FT aggregates in the absence of bound zinc;
FT when associated with S-7; S-58 and S-112.
FT CONFLICT 18 18 I -> S (in Ref. 3; no nucleotide entry).
FT CONFLICT 99 99 S -> V (in Ref. 3; no nucleotide entry).
FT STRAND 3 10
FT STRAND 12 14
FT STRAND 16 25
FT STRAND 26 28
FT STRAND 30 38
FT STRAND 41 50
FT HELIX 54 56
FT HELIX 58 61
FT STRAND 63 65
FT STRAND 67 69
FT STRAND 74 76
FT STRAND 77 79
FT STRAND 84 90
FT HELIX 92 94
FT STRAND 96 104
FT STRAND 106 108
FT HELIX 109 111
FT STRAND 112 115
FT STRAND 116 123
FT STRAND 127 129
FT STRAND 130 132
FT HELIX 133 136
FT TURN 138 140
FT STRAND 143 149
FT STRAND 151 153
SQ SEQUENCE 154 AA; 15936 MW; 25CA38DA8D564483 CRC64;
MATKAVCVLK GDGPVQGIIN FEQKESNGPV KVWGSIKGLT EGLHGFHVHE FGDNTAGCTS
AGPHFNPLSR KHGGPKDEER HVGDLGNVTA DKDGVADVSI EDSVISLSGD HCIIGRTLVV
HEKADDLGKG GNEESTKTGN AGSRLACGVI GIAQ
//

MIM 105400
*RECORD*
*FIELD* NO
105400
*FIELD* TI
#105400 AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1
;;AMYOTROPHIC LATERAL SCLEROSIS 1, FAMILIAL; FALS;;
read moreAMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL DOMINANT
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL RECESSIVE, INCLUDED;;
AMYOTROPHIC LATERAL SCLEROSIS, SPORADIC, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because 15 to 20% of cases of
familial amyotrophic lateral sclerosis (FALS), referred to here as ALS1,
are associated with mutations in the superoxide dismutase-1 gene (SOD1;
147450) on chromosome 21q22.1. Although most cases of SOD1-related
familial ALS follow autosomal dominant inheritance, rare cases of
autosomal recessive inheritance have been reported.

DESCRIPTION

Amyotrophic lateral sclerosis is a neurodegenerative disorder
characterized by the death of motor neurons in the brain, brainstem, and
spinal cord, resulting in fatal paralysis. ALS usually begins with
asymmetric involvement of the muscles in middle adult life.
Approximately 10% of ALS cases are familial (Siddique and Deng, 1996).
ALS is sometimes referred to as 'Lou Gehrig disease' after the famous
American baseball player who was diagnosed with the disorder.

Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews
of ALS. Some forms of ALS occur with frontotemporal dementia (FTD).

Familial ALS is distinct from a form of ALS with dementia reported in
cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck,
1980), in which the histology is different and dementia and parkinsonism
complicate the clinical picture.

- Genetic Heterogeneity of Amyotrophic Lateral Sclerosis

ALS is a genetically heterogeneous disorder, with several causative
genes and mapped loci.

ALS6 (608030) is caused by mutation in the FUS gene (137070) on
chromosome 16p11.2; ALS8 (608627) is caused by mutation in the VAPB gene
(605704) on chromosome 13; ALS9 (611895) is caused by mutation in the
ANG gene (105850) on chromosome 14q11; ALS10 (612069) is caused by
mutation in the TARDBP gene (605078) on 1p36.2; ALS11 (612577) is caused
by mutation in the FIG4 gene (609390) on chromosome 6q21; ALS12 (613435)
is caused by mutation in the OPTN gene (602432) on chromosome 10p; ALS14
(613954) is caused by mutation in the VCP gene (601023) gene on
chromosome 9p13-p12; ALS15 (300857) is caused by mutation in the UBQLN2
gene (300264) on chromosome Xp11.23-p11.1; ALS17 (614696) is caused by
mutation in the CHMP2B gene (609512) on chromosome 3p11; ALS18 (614808)
is caused by mutation in the PFN1 gene (176610) on chromosome 17p13.3;
ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on
chromosome 2q34; and ALS20 (615426) is caused by mutation in the HNRNPA1
gene (164017) on chromosome 12q13. See also FTDALS (105550), caused by
mutation in the C9ORF72 gene (614260) on chromosome 9p21.

Loci associated with the disorder are found on chromosomes 18q21 (ALS3;
606640) and 20p13 (ALS7; 608031).

Intermediate-length polyglutamine repeat expansions in the ATXN2 gene
(601517) contribute to susceptibility to ALS (ALS13; 183090).
Susceptibility to ALS has been associated with mutations in other genes,
including deletions or insertions in the gene encoding the heavy
neurofilament subunit (NEFH; 162230); deletions in the gene encoding
peripherin (PRPH; 170710); and mutations in the dynactin gene (DCTN1;
601143).

Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (205100),
caused by mutation in the alsin (606352) gene on 2q33; ALS4 (602433),
caused by mutation in the senataxin gene (SETX; 608465) on 9q34; and
ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13.
A locus on chromosome 15q15-q21.1 (ALS5; 602099) is associated with a
juvenile-onset form.

CLINICAL FEATURES

Horton et al. (1976) suggested that there are 3 phenotypic forms of
familial ALS, each inherited as an autosomal dominant disorder. The
first form they delineated is characterized by rapidly progressive loss
of motor function with predominantly lower motor neuron manifestations
and a course of less than 5 years. Pathologic changes are limited to the
anterior horn cells and pyramidal tracts. The second form is clinically
identical to the first, but at autopsy additional changes are found in
the posterior columns, Clarke column, and spinocerebellar tracts. The
third form is similar to the second except for a much longer survival,
usually beyond 10 and often 20 years. Examples of type 1 include the
families of Green (1960), Poser et al. (1965) and Thomson and Alvarez
(1969). Examples of type 2 include the families of Kurland and Mulder
(1955) and Engel et al. (1959). Engel et al. (1959) described 2 American
families, 1 of which was of Pennsylvania Dutch stock with at least 11
members of 4 generations affected with what was locally and popularly
termed 'Pecks disease.' Examples of type 3 include the families of Amick
et al. (1971) and Alberca et al. (1981). In the Spanish kindred reported
by Alberca et al. (1981), early onset and persistence of muscle cramps,
unilateral proximal segmental myoclonus, and early abolition of ankle
jerks were conspicuous clinical features.

Brown (1951, 1960) described 2 New England families, Wetherbee and Farr
by name, with autosomal dominant inheritance of a rapidly progressive
neurodegenerative disorder with loss of anterior horn cells of the
spinal cord and bulbar palsy. (See also Hammond, 1888 and
Myrianthopoulos and Brown, 1954). Neuropathology showed a classic
'middle-root zone' pattern of posterior column demyelination in addition
to involvement of the anteriolateral columns and ventral horn cells.
Although the disorder was clinically indistinguishable from ALS, the
pattern of posterior column demyelinations was unexpected. Osler (1880)
had described the Farr family earlier (McKusick, 1976). Variability in
disease severity in the Farr family was indicated by the case of a
78-year-old woman with relatively minor findings who had buried a son
and whose mother had been affected (Siddique, 1993).

Powers et al. (1974) reported the first autopsy in a member of the
Wetherbee family from Vermont. The patient was a 35-year-old woman who
began to experience weakness in the left leg 1 year before her terminal
admission. She then gradually developed weakness and atrophy of the left
hand, right lower limb, and right hand. One month before admission she
developed dyspnea which steadily worsened, and she was admitted to
hospital because of severe ventilatory insufficiency secondary to muscle
weakness. She showed atrophy of all extremities, areflexia, and, except
for slight movement of the left shoulder and right foot, quadriplegia.
The patient died on the second hospital day. Autopsy showed severe
demyelination type of atrophy of all muscles. Gray atrophy of the lumbar
and cervical anterior roots was evident grossly. Microscopic neuronal
changes included a moderate loss of neurons from the hypoglossal nuclei
and dorsal motor vagal nuclei, severe neuronal loss from the anterior
horns of the cervical and lumbar cord with reactive gliosis,
eosinophilic intracytoplasmic inclusions in many of the remaining lumbar
anterior horn cells, and a moderately symmetric loss of neurons from the
Clarke column. A severe asymmetric loss of axons and myelin was
demonstrated throughout the cervical dorsal spinocerebellar tracts and
lumbar posterior columns, with moderate loss in the lumbar lateral
corticospinal tracts. Powers et al. (1974) concluded that the disorder
corresponded exactly to a subgroup of familial ALS described by Hirano
et al. (1967). Engel (1976) concluded that the 'Wetherbee ail' and the
Farr family disease were consistent with ALS (Engel et al., 1959).

Alter and Schaumann (1976) reported 14 cases in 2 families and attempted
a refinement of the classification of hereditary ALS. Hudson (1981)
stated that posterior column disease is found in association with ALS in
80% of familial cases.

In a kindred with an apparently 'new' microcephaly-cataract syndrome
(212540), reported by Scott-Emuakpor et al. (1977), 10 persons had died
of a seemingly unrelated genetic defect--amyotrophic lateral sclerosis.

Veltema et al. (1990) described adult ALS in 18 individuals from 6
generations of a Dutch family. Onset occurred between ages 19 and 46;
duration of disease averaged 1.7 years. The clinical symptoms were
predominantly those of initial shoulder girdle and ultimate partial
bulbar muscle involvement.

Iwasaki et al. (1991) reported a Japanese family in which members in at
least 3 generations had ALS. At least 2 individuals in the family also
had Ribbing disease (601477), a skeletal dysplasia that was presumably
unrelated to the ALS.

INHERITANCE

Familial ALS caused by mutations in the SOD1 gene usually causes
autosomal dominant disease, but can also cause autosomal recessive ALS.

In Germany, Haberlandt (1963) concluded that ALS is an 'irregular'
autosomal dominant disorder in many instances. Gardner and Feldmahn
(1966) described adult-onset ALS in a family in which 15 members
spanning 7 generations were affected.

Husquinet and Franck (1980) reported a family with ALS suggesting
autosomal dominant inheritance with incomplete penetrance. Twelve men
and 6 women were affected; 4 unaffected members of the family
transmitted the disease. The first signs of the disease, which ran its
course in 5 to 6 years, were in either the arms or the legs. As in most
cases of ALS, death was caused by bulbar paralysis. Mean age at death
was about 57 years.

In a review of a familial ALS, de Belleroche et al. (1995) found
autosomal dominant inheritance with incomplete penetrance; by age 85
years, about 80% of carriers had manifested the disorder, and it was not
uncommon to see obligate carriers in a family who died without
manifesting the disease. Phenotypic heterogeneity was also common within
families: for example, age of onset varying over 30 years within a
family and duration of illness varying from 6 months to 5 years. Signs
at onset were variable, but the disease usually began with focal and
asymmetric wasting of hand muscles. Lower motor neuron involvement was
usually conspicuous, whereas involvement of upper motor neurons was less
marked.

Bradley et al. (2005) found no evidence for preferential maternal or
paternal transmission among 185 families in which at least 2 individuals
were diagnosed with ALS. Initial evidence suggesting anticipation was
rejected following further analysis.

By analysis of a Swedish multigeneration registry spanning from 1961 to
2005, Fang et al. (2009) identified 6,671 probands with ALS. There was a
17-fold increased risk for development of ALS among sibs, and a 9-fold
increased risk among children of probands. Sibs and children had a
greater risk if the proband was diagnosed at a younger age, and the risk
decreased with increasing age at diagnosis of the proband. Two cases
were identified among the cotwins of ALS probands, yielding a relative
risk of 32 for monozygotic twins. Spouses of probands had no
significantly increased risk compared to controls. The findings
indicated that there is a major genetic role in the development of ALS.

- Possible X-linked Inheritance

In a family with ALS reported by Wilkins et al. (1977), X-linked
dominant inheritance was suggested by the late onset in females and the
lack of male-to-male transmission.

Siddique et al. (1987) did linkage studies in a family with 13 affected
persons in 4 generations. There was no instance of male-to-male
transmission. Kunst (2004) referenced an X-linked dominant, late-onset
form linked to Xp11-q12 but reported only in abstract (Siddique et al.,
1998).

MAPPING

Siddique et al. (1989) presented preliminary data from genetic linkage
analysis in 150 families with familial ALS. Two regions of possible
linkage were identified on chromosomes 11 and 21. The highest lod score
observed was 1.46, obtained with D21S13 at theta = 0.20. The next
highest lod score was observed with marker D11S21 (lod score = 1.05 at
maximum theta of 0.001).

Siddique et al. (1991) presented evidence for linkage of familial ALS,
termed ALS1, to markers on chromosome 21q22.1-q22.2 (maximum lod score
of 5.03 10 cM telomeric to marker D21S58). Tests for heterogeneity in
these families yielded a probability of less than 0.0001 that of
genetic-locus heterogeneity, i.e., a low probability of homogeneity.

- Genetic Heterogeneity

King et al. (1993) failed to find linkage to loci on chromosome 21 in 8
U.K. families with ALS, indicating genetic heterogeneity.

- Associations Pending Confirmation

In a genomewide association study (GWAS) of 1,014 deceased patients with
sporadic ALS and 2,258 controls from the U.S. and Europe, Landers et al.
(2009) found a significant association between dbSNP rs1541160 in intron
8 of the KIFAP3 gene (601836) on chromosome 1q24 and survival (p = 1.84
x 10(-8), p = 0.021 after Bonferroni correction). Homozygosity for the
favorable allele, CC, conferred a 14-month survival advantage compared
to TT. There was linkage disequilibrium between dbSNP rs1541160 and
dbSNP rs522444 within the KIFAP3 promoter, and the favorable alleles of
both SNPs correlated with decreased KIFAP3 expression in brain. No SNPs
were associated with risk of sporadic ALS, site of onset, or age of
onset. The findings suggested that genetic factors may modify phenotypes
in ALS.

Van Es et al. (2009) conducted a genomewide association study among
2,323 individuals with sporadic ALS and 9,013 control subjects and
evaluated all SNPs with P less than 1.0 x 10(-4) in a second,
independent cohort of 2,532 affected individuals and 5,940 controls.
Analysis of the genomewide data revealed genomewide significance for 1
SNP, dbSNP rs12608932, with P = 1.30 x 10(-9). This SNP showed robust
replication in the second cohort, and a combined analysis over the 2
stages yielded P = 2.53 x 10(-14). The dbSNP rs12608932 SNP is located
at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A
(609894), which regulates the release of neurotransmitters such as
glutamate at neuromuscular synapses.

- Exclusion Studies

Wills et al. (2009) conducted a metaanalysis of 10 published studies,
including 4 GWAS, and 1 unpublished study that had reported findings on
association of sporadic ALS and paraoxonase (see PON1; 168820) SNPs on
chromosome 7q21.3. The metaanalysis found no association between
sporadic ALS and the PON locus and encompassed 4,037 ALS patients and
4,609 controls, including GWAS data from 2,018 ALS cases and 2,425
controls. The authors stated that this was the largest metaanalysis of a
candidate gene in ALS to date and the first ALS metaanalysis to include
data from GWAS.

PATHOGENESIS

Bradley and Krasin (1982) suggested that a defect in DNA repair may
underlie ALS.

Rothstein et al. (1992) found in in vitro studies that synaptosomes in
neural tissue obtained from 13 ALS patients showed a marked decrease in
the maximal velocity of transport for high-affinity glutamate uptake in
spinal cord, motor cortex, and somatosensory cortex compared to
controls. The decrease in glutamate uptake was not observed in tissue
from visual cortex, striatum, or hippocampus. Neural tissue from
patients with other neurodegenerative disorders did not show this
defect. In ALS tissue, there was no defect in affinity of the
transporter for glutamate and no decrease in the transport of other
molecules (gamma-aminobutyric acid and phenylalanine). Rothstein et al.
(1992) suggested that defects in a high-affinity glutamate transporter
(see, e.g., SLC1A1, 133550) could lead to neurotoxic levels of
extracellular glutamate, contributing to neurodegeneration in ALS.

Liu et al. (1998) demonstrated increased free radical production in the
spinal cord but not the brain of transgenic mice expressing mutant human
SOD1 (G93A; 147450.0008), which preceded the degeneration of motor
neurons. They hypothesized that in situ production of free radicals
initiates oxidative injury and that antioxidants that penetrate into the
central nervous system may be of therapeutic benefit.

Li et al. (2000) demonstrated an 81.5% elevation of caspase-1 (CASP1;
147678) activity in the spinal cord of humans with ALS when compared
with normal controls, and, using an animal model, suggested that
caspases play an instrumental role in the neurodegenerative processing
of ALS. Caspase inhibition using zVAD-fmk delayed disease onset and
mortality in the mouse model of ALS. Moreover, zVAD-fmk was found to
inhibit caspase-1 activity as well as caspase-1 and caspase-3 (600636)
mRNA upregulation, providing evidence for a non-cell-autonomous pathway
regulating caspase expression. The findings also showed that zVAD-fmk
decreased IL1-beta (147720), an indication that caspase-1 activity was
inhibited.

Okado-Matsumoto and Fridovich (2002) proposed a mechanism by which
missense mutations in SOD1 lead to ALS. They suggested that the binding
of mutant SOD1 to heat-shock proteins leads to formation of sedimentable
aggregates, making the heat shock proteins unavailable for their
antiapoptotic functions and leading ultimately to motor neuron death.

Kawahara et al. (2004) extracted RNA from single motor neurons isolated
with a laser microdissector from 5 individuals with sporadic ALS and 5
normal control subjects. GluR2 (GRIA2; 138247) RNA editing was 100%
efficient in the control samples, but the editing efficiency varied
between 0 and 100% in the motor neurons from each individual with ALS
and was incomplete in 44 (56%) of them. Mice transgenic for GluR2 made
artificially permeable to calcium ions developed motor neuron disease
late in life (Feldmeyer et al., 1999), indicating that motor neurons may
be specifically vulnerable to defective RNA editing. Kawahara et al.
(2004) suggested that defective GluR2 RNA editing at the Q/R site may be
relevant to ALS etiology.

Shibata et al. (1994) found SOD1-like immunoreactivity within Lewy
body-like inclusions in the spinal cords of 10 of 20 patients with
sporadic ALS. Skein-like inclusions and Bunina bodies, which were found
in all 20 ALS cases, showed no SOD1-like immunoreactivity.

He and Hays (2004) identified Lewy body-like ubiquitinated (see UBB;
191339) inclusions in motor neurons from 9 of 40 ALS patients; all of
the inclusions expressed peripherin. Similar inclusions were not
identified in 39 controls.

Neumann et al. (2006) identified TDP43 (605078) as the major disease
protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative
frontotemporal lobar degeneration (see 607485) and ALS. Pathologic TDP43
is hyperphosphorylated, ubiquitinated, and cleaved to generate
C-terminal fragments and was recovered only from affected CNS regions,
including hippocampus, neocortex, and spinal cord. Neumann et al. (2006)
concluded that TDP43 represents the common pathologic substrate linking
these neurodegenerative disorders.

In mice, Miller et al. (2006) demonstrated that human SOD1
mutant-mediated damage within muscles was not a significant contributor
to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of
muscle mass and strength provided no benefit in slowing disease onset or
progression.

Pradat et al. (2007) found muscle NOGOA (604475) expression in 17 of 33
patients with spinal lower motor neuron syndrome observed for 12 months.
NOGOA expression correctly identified patients who further progressed to
ALS with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was
detected as early as 3 months after symptom onset in patients who later
developed typical ALS. Pradat et al. (2007) suggested that muscle NOGOA
may be a prognostic marker for ALS in lower motor neuron syndromes.
Tagerud et al. (2007) and Askanas et al. (2007) both commented that
studies have demonstrated that NOGOA expression is increased in
denervated muscles in mouse models and in other human neuropathies and
myopathies. Both groups suggested that it may be premature to consider
NOGOA muscle expression as a specific biomarker for ALS, as suggested by
Pradat et al. (2007).

Using a specific antibody to monomer or misfolded forms of SOD1 (Rakhit
et al., 2007), Liu et al. (2009) detected monomer/misfolded SOD1 in
spinal cord sections of all 5 patients with familial ALS due to
mutations in the SOD1 gene. The antibody localized primarily to hyaline
conglomerate inclusions in motor neuron perikarya and occasionally to
neuritic processes. In contrast, no immunostaining was observed in
spinal cord tissue from ALS patients without SOD1 mutations, including
13 with sporadic disease and 1 with non-SOD1 familial ALS. The findings
indicated a distinct difference between familial ALS1 and sporadic ALS,
and supported the idea that monomer or misfolded SOD1 is not a common
disease mechanism.

Rabin et al. (2010) studied exon splicing directly in 12 sporadic ALS
and 10 control lumbar spinal cords. ALS patients had rostral onset and
caudally advancing disease and abundant residual motor neurons in this
region. Whole-genome exon splicing was profiled from RNA pools collected
from motor neurons and from the surrounding anterior horns. In the motor
neuron-enriched mRNA pool, there were 2 distinct cohorts of mRNA
signals, most of which were upregulated: 148 differentially expressed
genes and 411 aberrantly spliced genes. The aberrantly spliced genes
were highly enriched in cell adhesion, especially cell-matrix as opposed
to cell-cell adhesion. Most of the enriching genes encoded transmembrane
or secreted as opposed to nuclear or cytoplasmic proteins. The
differentially expressed genes were not biologically enriched. In the
anterior horn enriched mRNA pool, there were no clearly identified mRNA
signals or biologic enrichment. Rabin et al. (2010) suggested possible
mechanisms in cell adhesion for the contiguously progressive nature of
motor neuron degeneration.

Using unbiased transcript profiling in the Sod1G93A mouse model of ALS,
Lincecum et al. (2010) identified a role for the costimulatory pathway,
a key regulator of immune responses. Furthermore, Lincecum et al. (2010)
observed that this pathway is upregulated in the blood of 56% of human
patients with ALS.

Kudo et al. (2010) used laser capture microdissection coupled with
microarrays to identify early transcriptome changes occurring in spinal
cord motor neurons or surrounding glial cells in models of ALS. Two
transgenic mouse models of familial motor neuron disease, Sod1G93A and
TauP301L (157140.0001), were used at the presymptomatic stage.
Identified gene expression changes were predominantly model-specific.
However, several genes were regulated in both models. The relevance of
identified genes as clinical biomarkers was tested in the peripheral
blood transcriptome of presymptomatic Sod1G93A animals using
custom-designed ALS microarray. To confirm the relevance of identified
genes in human sporadic ALS (SALS), selected corresponding protein
products were examined by high-throughput immunoassays using tissue
microarrays constructed from human postmortem spinal cord tissues. Genes
that were identified by these experiments and were located within a
linkage region associated with familial ALS/frontotemporal dementia were
sequenced in several families. This large-scale gene and protein
expression study pointing to distinct molecular mechanisms of TAU- and
SOD1-induced motor neuron degeneration identified several novel
SALS-relevant proteins, including CNGA3 (600053), CRB1 (604210), OTUB2
(608338), MMP14 (600754), SLK (FYN; 137025), DDX58 (609631), RSPO2
(610575) and the putative blood biomarker Mgll (609699).

Pedrini et al. (2010) showed that the toxicity of mutant SOD1 (147450)
relies on its spinal cord mitochondria-specific interaction with BCL2
(151430). Mutant SOD1 induced morphologic changes and compromised
mitochondrial membrane integrity leading to the release of cytochrome c
only in the presence of BCL2. In cells and in mouse and human spinal
cord homogenates with SOD1 mutations, binding to mutant SOD1 triggered a
conformational change in BCL2 that resulted in the exposure of its BH3
domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain
failed to support mutant SOD1-mediated mitochondrial toxicity.

Meissner et al. (2010) found that G93A mutant SOD1 activated caspase-1
(CASP1; 147678) and CASP1-mediated secretion of mature IL1-beta (147720)
in a dose-dependent manner in microglia and macrophages. In cells in
which CASP1 was activated, there was rapid endocytosis of mutant SOD1
into the cytoplasm; autophagy of mutant SOD1 within the cytoplasm
dampened the proinflammatory response. Mutant SOD1 induced caspase
activation through a gain of amyloid conformation, not through its
enzymatic activity. Deficiency in caspase-1 or IL1-beta extended the
life span of mutant Sod1 mice and was associated with decreased
microgliosis and astrogliosis; however, age at disease onset was not
affected. Treatment of mutant mice with an IL1 receptor inhibitor also
extended survival and improved motor performance. The findings suggested
that IL1-beta contributes to neuroinflammation and disease progression
in ALS.

To determine whether increased SOD1 protects the heart from ischemia
Armakola et al. (2012) reported results from 2 genomewide
loss-of-function TDP43 (605078) toxicity suppressor screens in yeast.
The strongest suppressor of TDP43 toxicity was deletion of DBR1
(607024), which encodes an RNA lariat debranching enzyme. Armakola et
al. (2012) showed that, in the absence of DBR1 enzymatic activity,
intronic lariats accumulate in the cytoplasm and likely act as decoys to
sequester TDP43, preventing it from interfering with essential cellular
RNAs and RNA-binding proteins. Knockdown of DBR1 in a human neuronal
cell line or in primary rat neurons was also sufficient to rescue TDP43
toxicity. Armakola et al. (2012) concluded that their findings provided
insight into TDP43-mediated cytotoxicity and suggested that decreasing
DBR1 activity could be a potential therapeutic approach for ALS.

MOLECULAR GENETICS

- Autosomal Dominant Mutations

In affected members of 13 unrelated families with ALS, Rosen et al.
(1993) identified 11 different heterozygous mutations in exons 2 and 4
of the SOD1 gene (147450.0001-147450.0011). Deng et al. (1993)
identified 3 mutations in exons 1 and 5 of the SOD1 gene in affected
members of ALS families. Eight families had the same mutation (A4V;
147450.0012). One of the families with the A4V mutation was the Farr
family reported by Brown (1951, 1960).

Pramatarova et al. (1995) estimated that approximately 10% of ALS cases
are inherited as an autosomal dominant and that SOD1 mutations are
responsible for at least 13% of familial ALS cases.

Jones et al. (1993) demonstrated that mutation in the SOD1 gene can also
be responsible for sporadic cases of ALS. They found the same mutation
(I113T; 147450.0011) in 3 of 56 sporadic cases of ALS drawn from a
population-based study in Scotland.

Among 233 sporadic ALS patients, Broom et al. (2004) found no
association between disease susceptibility or phenotype and a deletion
and 4 SNPs spanning the SOD1 gene, or their combined haplotypes, arguing
against a major role for wildtype SOD1 in sporadic ALS.

In a review of familial ALS, de Belleroche et al. (1995) listed 30
missense mutations and a 2-bp deletion in the SOD1 gene. Siddique and
Deng (1996) reviewed the genetics of ALS, including a tabulation of SOD1
mutations in familial ALS.

Millecamps et al. (2010) identified 18 different SOD1 missense mutations
in 20 (12.3%) of 162 French probands with familial ALS. Compared to
those with ALS caused by mutations in other genes, those with SOD1
tended to have disease onset predominantly in the lower limbs. One-third
of SOD1 patients survived for more than 7 years: these patients had an
earlier disease onset compared to those presenting with a more rapid
course. No patients with SOD1 mutations developed cognitive impairment.

- Autosomal Recessive Mutations

Andersen et al. (1995) found homozygosity for a mutation in the SOD1
gene (D90A; 147450.0015) in 14 ALS patients from 4 unrelated families
and 4 apparently sporadic ALS patients from Sweden and Finland.
Consanguinity was present in several of the families, consistent with
autosomal recessive inheritance. Erythrocyte SOD1 activity was
essentially normal. The findings suggested that this mutation caused ALS
by a gain of function rather than by loss, and that the D90A mutation
was less detrimental than previously reported mutations. Age at onset
ranged from 37 to 94 years in 1 family in which all patients showed very
similar disease phenotypes; symptoms began with cramps in the legs,
which progressed to muscular atrophy and weakness. Upper motor neuron
signs appeared after 1 to 4 years' disease duration in all patients, and
none of the patients showed signs of intellectual impairment. In a
second family, onset in 2 sibs was at the age of 40, with a phenotype
like that in the first family. In a third family, 3 sibs had onset at
ages 20, 36, and 22 years, respectively. Thus, familial ALS due to
mutation in the SOD1 gene exists in both autosomal dominant and
autosomal recessive forms. Al-Chalabi et al. (1998) concluded that a
'tightly linked protective factor' in some families modifies the toxic
effect of the mutant SOD1, resulting in recessive inheritance.

- Susceptibility Genes and Association Studies

Siddique et al. (1998) could demonstrate no relationship between APOE
genotype (107741) and sporadic ALS. Previous studies had resulted in
contradictory results. Siddique et al. (1998) found no significant
difference in age at onset between patients with 1, 2, or no APOE*4
alleles.

In 1 of 189 ALS patients, Gros-Louis et al. (2004) identified a 1-bp
deletion in the peripherin gene (170710.0001), suggesting that the
mutation conferred an increased susceptibility to development of the
disease.

Among 250 patients with a putative diagnosis of ALS, Munch et al. (2004)
identified 3 mutations in the DCTN1 gene (601143.0002-601143.0004) in 3
families. One of the mutations showed incomplete penetrance. The authors
suggested that mutations in the DCTN1 gene may be a susceptibility risk
factor for ALS.

Veldink et al. (2005) presented evidence suggesting that SMN genotypes
producing less SMN protein increased susceptibility to and severity of
ALS. Among 242 ALS patients, the presence of 1 SMN1 (600354) copy, which
represents spinal muscular atrophy (SMA; 253300) carrier status, was
significantly increased in patients (6.6%) compared to controls (1.7%).
The presence of 1 copy of SMN2 (601627) was significantly increased in
patients (58.7%) compared to controls (29.7%), whereas 2, 3, or 4 SMN2
copies were significantly decreased in patients compared to controls.

In 167 ALS patients and 167 matched controls, Corcia et al. (2002) found
that 14% of ALS patients had an abnormal copy number of the SMN1 gene,
either 1 or 3 copies, compared to 4% of controls. Among 600 patients
with sporadic ALS, Corcia et al. (2006) found an association between
disease and 1 or 3 copies of the SMN1 gene (p less than 0.0001; odds
ratio of 2.8). There was no disease association with SMN2 copy number.

Dunckley et al. (2007) provided evidence suggestive of an association
between the FLJ10986 gene (611370) on chromosome 1 and sporadic
amyotrophic lateral sclerosis in 3 independent patient populations. The
susceptibility allele of dbSNP rs6690993 conferred an odds ratio of 1.35
(p = 3.0 x 10(-4)).

Simpson et al. (2009) performed a multistage association study using
1,884 microsatellite markers in 3 populations totaling 781 ALS patients
and 702 control individuals. They identified a significant association
(p = 1.96 x 10(-9)) with the 15-allele marker D8S1820 in intron 10 of
the ELP3 gene (612722). Fine mapping with SNPs in and around the ELP3
gene identified a haplotype consisting of allele 6 of D8S1820 and dbSNP
rs12682496 strongly associated with ALS (p = 1.05 x 10(-6)).

Lambrechts et al. (2009) performed a metaanalysis of 11 published
studies comprising over 7,000 individuals examining a possible
relationship between variation in the VEGF gene (192240) and ALS. After
correction, no specific genotypes or haplotypes were significantly
associated with ALS. However, subgroup analysis by gender found that the
-2578AA genotype (dbSNP rs699947; 192240.0002), which lowers VEGF
expression, increased the risk of ALS in males (odds ratio of 1.46),
even after correction for publication bias and multiple testing.

Sabatelli et al. (2009) identified nonsynonymous variants in the CHRNA3
(118503) and CHRNB4 (118509) genes on chromosome 15q25.1 and the CHRNA4
gene (118504) on chromosome 20q13.2-q13.3, encoding neuronal nicotinic
acetylcholine receptor (nAChR) subunits, in 19 sporadic ALS patients and
in 14 controls. NAChRs formed by mutant alpha-3 and alpha-4 and wildtype
beta-4 subunits exhibited altered affinity for nicotine (Nic), reduced
use-dependent rundown of Nic-activated currents, and reduced
desensitization leading to sustained intracellular calcium
concentration, in comparison with wildtype nAChR. Sabatelli et al.
(2009) suggested that gain-of-function nAChR variants may contribute to
disease susceptibility in a subset of ALS patients because calcium
signals mediate the neuromodulatory effects of nAChRs, including
regulation of glutamate release and control of cell survival.

In a 3-generation kindred with familial ALS, Mitchell et al. (2010)
found linkage to markers D12S1646 and D12S354 on chromosome 12q24
(2-point lod score of 2.7). Screening of candidate genes identified a
heterozygous arg199-to-trp (R199W) mutation in exon 7 of the DAO gene
(124050) in 3 affected members and in 1 obligate carrier, who died at
age 73 years of cardiac failure and reportedly had right-sided weakness
and dysarthria. The proband had onset at age 40, and the mean age at
death in 7 cases was 44 years (range, 42 to 55 years). The mutation was
also present in 3 at-risk individuals of 33, 44, and 48 years of age,
respectively. The R199W mutation was not found in 780 Caucasian
controls. Postmortem examination of the obligate carrier showed some
loss of motor neurons in the spinal cord and degeneration of 1 of the
lateral corticospinal tracts. There was markedly decreased DAO enzyme
activity in the spinal cord compared to controls. Coexpression of mutant
protein with wildtype protein in COS-7 cells indicated a
dominant-negative effect for the mutant protein. Rat neuronal cell lines
expressing the R199W-mutant protein showed decreased viability and
increased ubiquitinated aggregates compared to wildtype. Mitchell et al.
(2010) suggested a role for the DAO gene in ALS, but noted that a causal
role for the R199W-mutant protein remained to be unequivocally
established.

In a study of 847 patients with ALS and 984 controls, Blauw et al.
(2012) found that SMN1 duplications were associated with increased
susceptibility to ALS (odds ratio (OR) of 2.07; p = 0.001). A
metaanalysis with previous data including 3,469 individuals showed a
similar effect, with an OR of 1.85 (p = 0.008). SMN1 deletions or point
mutations and SMN2 copy number status were not associated with ALS, and
SMN1 or SMN2 copy number variants had no effect on survival or the age
at onset of the disease.

- Modifier Genes

Giess et al. (2002) reported a 25-year-old man with ALS who died after a
rapid disease course of only 11 months. Genetic analysis identified a
heterozygous mutation in the SOD1 gene and a homozygous mutation in the
ciliary neurotrophic factor gene (CNTF; 118945.0001). The patient's
mother, who developed ALS at age 54, had the SOD1 mutation and was
heterozygous for the CNTF mutation. His healthy 35-year-old sister had
the SOD1 mutation, but did not have the CNTF mutation. Two maternal
aunts had died from ALS at 56 and 43 years of age, and a maternal
grandmother and a great-grandmother had died from progressive muscle
weakness and atrophy at ages 62 and less than 50 years, respectively.
Giess et al. (2002) found that transgenic SOD1 mutant mice who were
Cntf-deficient had a significantly earlier age at disease onset compared
to in transgenic mice that were wildtype for CNTF. Although linkage
analysis in mice revealed that the SOD1 gene was solely responsible for
the disease, disease onset as a quantitative trait was regulated by the
CNTF locus. In addition, patients with sporadic ALS who had a homozygous
CNTF gene defect showed significantly earlier disease onset, but did not
show a significant difference in disease duration. Giess et al. (2002)
concluded that CNTF acts as a modifier gene that leads to early onset of
disease in patients with SOD1 mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

De Belleroche et al. (1995) noted that the SOD1 H46R mutation
(147450.0013) was associated with a more benign form of ALS with average
duration of 17 years and only slightly reduced levels of SOD1 enzyme
activity. The authors referred to a family with an I113T mutation
(147450.0011) in which 1 affected member of the family died after a
short progression and another member survived more than 20 years.

Cudkowicz et al. (1997) registered 366 families in a study of dominantly
inherited ALS. They screened 290 families for mutations in the SOD1 gene
and detected mutations in 68 families; the most common SOD1 mutation,
A4V (147450.0012), was present in 50% of the families. The presence of
either of 2 SOD1 mutations, G37R (147450.0001) or L38V (147450.0002),
predicted an earlier age at onset. Additionally, the presence of the A4V
mutation correlated with shorter survival, whereas G37R, G41D
(147450.0004), and G93C (147450.0007) mutations predicted longer
survival. The clinical characteristics of patients with familial ALS
arising from SOD1 mutations were similar to those without SOD1 defects.
However, Cudkowicz et al. (1997) reported that mean age at onset was
earlier in the SOD1 group than in the non-SOD1 group, and Kaplan-Meier
plots demonstrated shorter survival in the SOD1 group compared with the
non-SOD1 group at early survival times.

Sato et al. (2005) measured the ratio of mutant-to-normal SOD1 protein
in 29 ALS patients with mutations in the SOD1 gene. Although there was
no relation to age at onset, turnover of mutant SOD1 was correlated with
a shorter disease survival time.

Regal et al. (2006) reported the clinical features of 20 ALS patients
from 4 families with the SOD1 G93C mutation (147450.0007). Mean age at
onset was 45.9 years, and all patients had slowly progressive weakness
and atrophy starting in the distal lower limbs. Although symptoms
gradually spread proximally and to the upper extremities, bulbar
function was preserved. None of the patients developed upper motor
neuron signs. Postmortem findings of 1 patient showed severe loss of
anterior horn cells and loss of myelinated fibers in the posterior
column and spinocerebellar tracts, but only mild changes in the lateral
corticospinal tracts. Lipofuscin and hyaline inclusions were observed in
many neurons. Patients with the G93C mutation had significantly longer
survival compared to patients with other SOD1 mutations.

CLINICAL MANAGEMENT

Amyotrophic lateral sclerosis is a disorder that has prominently been
mentioned as justification for assisted suicide. Ganzini et al. (1998)
found that in the states of Oregon and Washington most patients with ALS
whom they surveyed would consider assisted suicide. Many would request a
prescription for a lethal dose of medication well before they intended
to use it. Rowland (1998) reviewed the question of what it is about ALS
that raised the question of suicide. The progressive paralysis leads to
increase of loss of function, culminating in complete dependence on the
help of others for all activities of daily living and, if life is
sustained by assisted ventilation, loss of the ability to communicate or
swallow. Ten percent of patients are under the age of 40 years. Some
patients, wanting to live as long as possible, opted for tracheostomy
and assisted ventilation at home. In a study of 92 patients receiving
long-term assisted ventilation with tracheostomy, 20 lived for 8 to 17
years with the tracheostomy, and 9 became 'locked in' (they were
conscious but severely paralyzed and unable to communicate except by eye
movements). In the Oregon series, however, only 2 patients opted for
tracheostomy with long-term mechanical ventilation, and among patients
at the ALS Center at Columbia Presbyterian Medical Center, only 2.9%
chose it (Rowland, 1998). The last year in the life of an ALS victim,
Professor Morris Schwartz, was chronicled in a bestselling book written
by Albom (1997).

In a prospective randomized control trial of 44 ALS patients, Fornai et
al. (2008) reported that treatment of 16 patients with lithium plus
riluzole resulted in slower disease progression compared to 28 patients
treated with riluzole alone. All 16 patients treated with lithium
survived for 15 months; 29% of the patients receiving riluzole alone did
not survive by this endpoint. Studies in transgenic ALS mice showed a
similar delay in disease progression and longer survival. Mice treated
with lithium showed delayed cell death in spinal cord motor neurons,
increased numbers of normal mitochondria in motor neurons, decreased
SOD1 aggregation, and decreased reactive astrogliosis. Studies of
cultured mutant murine motor neurons suggested that lithium treatment
increased endosomal autophagy of aggregated proteins or abnormal
mitochondria, which may have contributed to the observed neuroprotective
effects.

POPULATION GENETICS

In 2 regions of northwestern Italy with a total population of
approximately 4.5 million, the Piemonte and Valle d'Aosta Register for
Amyotrophic Lateral Sclerosis (2001) determined a mean annual incidence
rate of 2.5 per 100,000 from 1995 to 1996. The data were comparable to
similar studies in other Western countries, suggesting diffuse genetic
or environmental factors in the pathogenesis of ALS.

Chio et al. (2008) found that 5 of 325 patients with ALS in Turin
province of the Piemonte region of Italy had mutations in the SOD1 gene.
Mutations were identified in 3 (13.6%) of 22 patients with a family
history of ALS, and 2 (0.7%) of 303 sporadic cases. Chio et al. (2008)
noted that the frequency of FALS (5.7%) was lower in this
population-based series compared to series reported from ALS referral
centers.

ANIMAL MODEL

See also ANIMAL MODEL in 147450.

The murine Mnd (motor neuron degeneration) mutation causes a late-onset,
progressive degeneration of upper and lower motor neurons. Using
endogenous retroviruses as markers, Messer et al. (1992) mapped the Mnd
gene in the mouse to proximal chromosome 8. Messer et al. (1992)
suggested that examination of human chromosome 8, which shows homology
of synteny, in human kindreds with ALS as well as related hereditary
neurologic diseases might be fruitful. They presented evidence
suggesting that a combination of genetic and environmental modifiers can
alter the time course of the phenotypic expression in the mouse model.

Gurney et al. (1994) found that expression of high levels of human SOD
containing the gly93-to-ala mutation (G93A; 147450.0008), a change that
had little effect on enzyme activity, resulted in motor neuron disease
in transgenic mice. The mice became paralyzed in one or more limbs as a
result of motor neuron loss from the spinal cord and died by 5 to 6
months of age. Ongoing reinnervation and remodeling of muscle
innervation suggested that 'sprouting' probably compensates for the loss
of motor neurons until late in the course of the disease. Gurney et al.
(1994) suggested that the toxicity of SOD1 from motor neurons could
involve the formation of the strong oxidant peroxynitrite from oxygen
and nitric oxide free radicals, representing a dominant,
gain-of-function role for SOD1 mutations in the pathogenesis of familial
ALS. The fact that mice with the abnormal human SOD became paralyzed
even though copies of the animals' own normal Sod gene remained intact
supported the gain-of-function role. Gurney et al. (1994) and other
groups studying transgenic mice found that animals making the highest
amounts of mutant Sod proteins were the ones that become paralyzed, a
finding that runs counter to the idea that decreased SOD activity is at
fault in ALS.

Wong et al. (1995) generated transgenic mice carrying a gly37-to-arg
(G37R; 147450.0001) mutation in the SOD1 gene associated with a subset
of familial ALS cases. The mice developed severe, progressive motor
neuron disease and provided an animal model for ALS. Wong et al. (1995)
observed that at lower levels of mutant accumulation, pathology was
restricted to lower motor neurons, whereas higher levels caused more
severe abnormalities and affected a variety of other neuronal
populations. The authors noted that the most obvious cellular
abnormality in the mutant mice was the presence in axons and dendrites
of membrane-bound vacuoles, which they hypothesized were derived from
degenerating mitochondria. Wong et al. (1995) concluded that the disease
in mice expressing G37R arises from the acquisition of an adverse
property by the mutant enzyme rather than elevation or loss of SOD1
activity.

Ripps et al. (1995) produced a transgenic mouse model of familial ALS by
introducing an SOD1 mutation (gly86-to-arg). In 2 lines of mice that
produced high levels of transgene mRNA in the CNS, motor paralysis
developed and was associated with degenerative changes of motor neurons
within the spinal cord, brainstem, and neocortex. Biochemical
measurements in these animals revealed no diminution of Sod activity,
indicating a dominant gain-of-function mutation. Tu et al. (1996)
reported that transgenic mice expressing a human SOD1 gene containing
the G92A mutation developed a motor neuron disease similar to familial
ALS, but transgenic mice expressing a wildtype human SOD1 transgene did
not. Neurofilament (NF)-rich inclusions in spinal motor neurons are
characteristic of ALS. Tu et al. (1996) found that such inclusions were
detectable in spinal cord motor neurons of the mutant carrying
transgenic mice at 82 days of age and about the time that the mice first
showed clinical evidence of the disease. In contrast, NF inclusions were
not seen in the mice with the wildtype transgene until they were 132
days old, and ubiquitin immunoreactivity, which likewise started at
about 82 days in mutant-bearing mice, was not increased in wildtype mice
even at 199 days of age. A striking similarity between the cytoskeletal
pathology of the mutant transgenic mice and the patients with ALS was
demonstrated.

Using immunohistochemistry and immunoblot experiments, Nguyen et al.
(2001) found that the p25/p35 (see 603460) ratio and Cdk5 (123831)
activity were abnormally elevated in the spinal cord of transgenic mice
with the G37R mutation in SOD1 (Wong et al., 1995). This elevation was
associated with the hyperphosphorylation of neurofilament and tau
(157140) proteins. By analyzing transgenic mouse lines with differing
G37R transgene expression levels, Nguyen et al. (2001) observed a
correlation between Cdk5 activity and the longevity of the mutant mice.
Nguyen et al. (2001) bred the G37R transgene onto neurofilament mutant
backgrounds and observed that the absence of neurofilament light subunit
(NEFL; 162280) provoked an accumulation of unassembled neurofilament
subunits in the perikaryon of motor neurons and extended the average
life span of the mutant mice. Using double immunofluorescence
microscopy, Nguyen et al. (2001) confirmed that Cdk5 and p25 colocalized
with perikaryal neurofilament accumulations in G37R mice on the
neurofilament mutant background. Using immunoblotting, Nguyen et al.
(2001) observed that the occurrence of perikaryal neurofilament
accumulations in the mutant mice was associated with a reduction in the
elevated phosphorylation of tau, another p25/cdk5 substrate. Nguyen et
al. (2001) hypothesized that perikaryal accumulations of neurofilament
proteins in motor neurons may alleviate ALS pathogenesis in SOD1(G37R)
mice by acting as a phosphorylation sink for Cdk5 activity, thereby
reducing the detrimental hyperphosphorylation of tau and other neuronal
substrates.

LaMonte et al. (2002) generated a mouse model of ALS by overexpressing
dynamitin (DCTN2; 607376) in postnatal motor neurons of transgenic mice.
They found that dynamitin overexpression disrupted the dynein-dynactin
complex, resulting in an inhibition of retrograde axonal transport. The
authors observed a late-onset, slowly progressive motor neuron
degenerative disease characterized by muscle weakness, spontaneous
trembling, abnormal posture and gaits, and deficits in strength and
endurance. LaMonte et al. (2002) detected histologic changes in spinal
cord motor neurons and skeletal muscle indicative of degeneration of
motor neurons and denervation atrophy of muscle. The transgenic mice
also displayed neurofilament accumulations. LaMonte et al. (2002)
concluded that their mouse model confirms the critical role of disrupted
axonal transport in the pathogenesis of motor neuron degenerative
disease.

Raoul et al. (2002) showed that Fas (134637), a member of the death
receptor family, triggers cell death specifically in motor neurons by
transcriptional upregulation of neuronal nitric oxide synthase (nNOS;
163731) mediated by p38 kinase (600289). ASK1 (602448) and Daxx (603186)
act upstream of p38 in the Fas signaling pathway. The authors also
showed that synergistic activation of the NO pathway and the classic
FADD (602457)/caspase-8 (601763) cell death pathway were needed for
motor neuron cell death. No evidence for involvement of the Fas/NO
pathway was found in other cell types. Motor neurons from transgenic
mice expressing ALS-linked SOD1 mutations displayed increased
susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002)
emphasized that this signaling pathway was unique to motor neurons and
suggested that these cell death pathways may contribute to motor neuron
loss in ALS. Raoul et al. (2006) reported that exogenous NO triggered
expression of Fas ligand (FASL; 134638) in cultured motoneurons. In
motoneurons from ALS model mice with mutations in the SOD1 gene, this
upregulation resulted in activation of Fas, leading through Daxx and p38
to further NO synthesis. The authors suggested that chronic low
activation of this feedback loop may underlie the slowly progressive
motoneuron loss characteristic of ALS.

To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2
subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid (AMPA)-type glutamate receptors (see GLUR2, 138247) to SOD1-related
motoneuronal death, Tateno et al. (2004) generated choline
acetyltransferase (ChAT; 118490)-GluR2 transgenic mice with
significantly reduced Ca(2)+ permeability of these receptors in spinal
motoneurons. Crossbreeding of the SOD1(G93A) transgenic mouse model of
ALS with ChAT-GluR2 mice led to marked delay of disease onset,
mortality, and the pathologic hallmarks such as release of cytochrome c
from mitochondria, induction of cox2 (600262), and astrogliosis.
Subcellular fractionation analysis revealed that unusual SOD1 species
accumulated in 2 fractions (P1, composed of nuclei and certain kinds of
cytoskeletons such as neurofilaments and glial fibrillary acidic protein
(GFAP; 137780), and P2, composed of mitochondria) long before disease
onset and then extensively accumulated in the P1 fractions by disease
onset. All these processes for unusual SOD1 accumulation were
considerably delayed by GluR2 overexpression. Ca(2+) influx through
atypical motoneuronal AMPA receptors thus promoted a misfolding of
mutant SOD1 protein and eventual death of these neurons.

Using mice carrying a deletable mutant Sod1 gene, Boillee et al. (2006)
demonstrated that expression within motor neurons is a primary
determinant of ALS disease onset and of an early phase of disease
progression. Diminishing the mutant levels in microglia had little
effect on the early phase but sharply slowed later disease progression.
Boillee et al. (2006) concluded that onset and progression thus
represent distinct ALS disease phases defined by mutant action within
different cell types to generate non-cell autonomous killing of motor
neurons; their findings validate therapies, including cell replacement,
targeted to the nonneuronal cells.

Miller et al. (2006) demonstrated that human SOD1 mutant-mediated damage
within muscles of mice was not a significant contributor to
non-cell-autonomous pathogenesis of ALS. In addition, enhancement of
muscle mass and strength provided no benefit in slowing disease onset or
progression.

Marden et al. (2007) evaluated the effects of NADPH oxidase-1 (NOX1;
300225) or Nox2 (CYBB; 300481) deletion on transgenic mice
overexpressing human SOD1 with the G93A mutation by monitoring the onset
and progression of disease using various indices. Disruption of either
Nox1 or Nox2 significantly delayed progression of motor neuron disease
in these mice. However, 50% survival rates were enhanced significantly
more by Nox2 deletion than Nox1 deletion. Female mice lacking 1 copy of
the X-chromosomal Nox1 or Nox2 genes also exhibited significantly
increased survival rates, suggesting that in the setting of random
X-inactivation, a 50% reduction in Nox1- or Nox2-expressing cells has a
substantial therapeutic benefit in ALS mice. Marden et al. (2007)
concluded that NOX1 and NOX2 contribute to the progression of ALS.

Kieran et al. (2007) detected a significant upregulation of Puma (BBC3;
605854), a proapoptotic protein, in motoneurons of G93A-mutant mice
before symptom onset. Deletion of Puma in these mice improved motoneuron
survival and delayed disease onset and motor dysfunction, but did not
extend life span. The findings suggested that Puma may play a role in
the early stages of neurodegeneration in ALS by increasing ER
stress-mediated apoptosis.

Awano et al. (2009) found that canine degenerative myelopathy, a
spontaneously occurring adult-onset neurodegenerative disease, was
highly associated with a homozygous glu40-to-lys (E40K) mutation in the
canine Sod1 gene. The mutation was found in affected breeds including
Pembroke Welsh corgi, boxer, Rhodesian ridgeback, Chesapeake Bay
retriever, and German shepherd. The disorder was characterized
clinically by adult onset of spasticity and proprioceptive ataxia,
followed by weakness, paraplegia, and hyporeflexia. Histopathologic
examination of the spinal cord of 46 affected dogs showed white matter
degeneration with axonal and myelin loss and cytoplasmic Sod1-positive
inclusions in surviving neurons. The disorder closely resembled human
ALS.

Tateno et al. (2009) demonstrated that, starting from the pre-onset
stage of ALS, misfolded SOD1 species associated specifically with Kap3
(KIFAP3; 601836) in the ventral white matter of SOD1G93A-transgenic
mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding
to cargoes including ChAT. Motor axons in SOD1G93A-Tg mice also showed a
reduction in ChAT transport from the pre-onset stage. Using a purified
hybrid mouse neuroblastoma/rat glioma cell line NG108-15 transfected
with SOD1 mutations, the authors showed that microtubule-dependent
release of acetylcholine was significantly impaired by misfolded SOD1
species and that impairment was normalized by KAP3 overexpression. KAP3
was incorporated into SOD1 aggregates in spinal motor neurons from human
ALS patients as well. Tateno et al. (2009) suggested that KAP3
sequestration by misfolded SOD1 species and the resultant inhibition of
ChAT transport play a role in the pathophysiology of ALS.

Wong and Martin (2010) created transgenic mice expressing wildtype, G37R
(147450.0001), and G93A (147450.0008) human SOD1 in only skeletal
muscle. These mice developed age-related neurologic and pathologic
phenotypes consistent with ALS. Affected mice showed limb weakness and
paresis with motor deficits. Skeletal muscles developed severe pathology
involving oxidative damage, protein nitration, myofiber cell death, and
marked neuromuscular junction abnormalities. Spinal motor neurons
developed distal axonopathy, formed ubiquitinated inclusions, and
degenerated through an apoptotic-like pathway involving caspase-3
(600636). Mice expressing wildtype and mutant forms of SOD1 developed
motor neuron pathology. The authors concluded that SOD1 in skeletal
muscle has a causal role in ALS, and they proposed a nonautonomous
mechanism to explain the degeneration and selective vulnerability of
these motor neurons.

- Therapeutic Strategies

Transgenic mice overexpressing a mutated form of human SOD1 with a
gly93-to-ala substitution (G93A; 147450.0008) develop progressive muscle
wasting and paralysis as a result of spinal motor neuron loss and die at
5 to 6 months. Bordet et al. (2001) found that intramuscular injection
of an adenoviral vector encoding CTF1 (600435) in SOD1(G93A) newborn
mice delayed the onset of motor impairment as assessed in the rotarod
test. By CTF1 treatment, axonal degeneration was slowed, skeletal muscle
atrophy was largely reduced, and the time-course of motor impairment was
significantly decreased.

In a transgenic mouse model of ALS with the human G93A SOD1 mutation,
Drachman et al. (2002) demonstrated that treatment with the
cyclooxygenase-2 (COX2; 600262) inhibitor celecoxib resulted in
significant delay of onset of weakness and weight loss, prolonged
survival, preservation of ventral gray neurons in the spinal cord, and
reduced spinal cord astroglial and microglial proliferation. The authors
suggested that COX2 inhibition prevents prostaglandin-mediated release
of glutamate from astrocytes and interrupts the inflammatory processes
that result in the production of toxic reactive oxygen species.

Adeno-associated virus (AAV) can be retrogradely transported efficiently
from muscle to motor neurons of the spinal cord (Davidson et al., 2000;
Boulis et al., 2003). In the Sod1-overexpressing model of ALS in the
mouse, Kaspar et al. (2003) found that IGF1 (147440) administered
through an AAV vector by intramuscular injection into hindlimb
quadriceps and intercostal muscles at 60 days of age, approximately 30
days prior to disease onset, delayed onset by 31 days, twice as long as
that seen in mice given GDNF (600837) through an AAV vector.
GDNF-treated animals showed a smaller, 11-day increase in median
survival compared to GFP-treated controls. IGF1-treated animals showed a
larger, significant improvement in life span, with a 37-day increase in
median survival compared to controls. The maximal life span of
IGF1-treated animals was 265 days, compared to 140 days in the control
group. Kaspar et al. (2003) concluded that injection of IGF1 not only
delayed the onset of disease but also slowed the rate of disease
progression. In contrast, GDNF appeared only to have delayed the onset
of symptoms. IGF1 treatment was even able to expand life span when
administered after disease onset at 90 days of age.

Azzouz et al. (2004) reported that a single injection of a vascular
endothelial growth factor (VEGF; 192240)-expressing lentiviral vector
into various muscles delayed onset and slowed progression of ALS in mice
engineered to overexpress the gene encoding the mutated G93A form of
SOD1 (147450.0008), even when treatment was initiated at the onset of
paralysis. VEGF treatment increased the life expectancy of ALS mice by
30% without causing toxic side effects, thereby achieving one of the
most effective therapies reported in the field to that time. Storkebaum
et al. (2005) found that intracerebroventricular delivery of recombinant
Vegf in a rat model of ALS with the G93A SOD1 mutation delayed onset of
paralysis by 17 days, improved motor performance, and prolonged survival
by 22 days. By protecting cervical motoneurons, intracerebroventricular
delivery of Vegf was particularly effective in rats with the most severe
form of disease ALS with forelimb onset, which may be analogous to
patients with bulbar onset of ALS.

Urushitani et al. (2007) reported that active vaccination with mutant
SOD1 and passive immunization with anti-SOD1 antibody were effective in
alleviating disease symptoms and delaying mortality of in ALS mice with
a G37R SOD1 mutation and moderate expression of the mutant gene. Western
blot analysis showed clearance of SOD1 species in the spinal cord of
vaccinated mice. Vaccination was not effective in a different mouse
strain with extreme overexpression of mutant SOD1. The results were
consistent with the hypothesis that neurotoxicity of extracellular
secreted SOD1 may also play a role in disease pathogenesis.

Dimos et al. (2008) generated induced pluripotent stem (iPS) cells from
skin fibroblasts collected from an 82-year-old woman diagnosed with a
familial form of ALS caused by a mutation in the SOD1 gene (L144F;
147450.0017). These patient-specific iPS cells possessed properties of
embryonic stem cells and were successfully directed to differentiate
into motor neurons, the cell type destroyed in ALS.

Williams et al. (2009) showed that a key regulator of signaling between
motor neurons and skeletal muscle fibers is miR206 (611599), a skeletal
muscle-specific microRNA that is dramatically induced in the mouse model
of ALS. Mice that are genetically deficient in miR206 form normal
neuromuscular synapses during development, but deficiency of miR206 in
the ALS mouse model accelerates disease progression. miR206 is required
for efficient regeneration of neuromuscular synapses after acute nerve
injury, which probably accounts for its salutary effects in ALS. miR206
mediates these effects at least in part through histone deacetylase 4
(605314) and fibroblast growth factor (see 131220) signaling pathways.
Thus, Williams et al. (2009) concluded that miR206 slows ALS progression
by sensing motor neuron injury and promoting the compensatory
regeneration of neuromuscular synapses.

Based on their demonstration that the costimulatory pathway is activated
in multiple tissues in the Sod1(G93A) preclinical model of ALS as well
as in the blood of a subset of individuals with ALS, Lincecum et al.
(2010) developed a therapy using a monoclonal antibody to CD40L
(300386). Weight loss was slowed, paralysis delayed, and survival
extended in an ALS mouse model.

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84. Phillips, J.; Pyeritz, R.; Brooks, B.; Rosenthal, G.; Weintraub,
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86. Poser, C. M.; Johnson, M.; Bunch, L. D.: Familial amyotrophic
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87. Powers, J. M.; Horoupian, D. S.; Schaumburg, H. H.: Wetherbee
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88. Pradat, P.-F.; Bruneteau, G.; Gonzalez de Aguilar, J.-L.; Dupuis,
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89. Pramatarova, A.; Figlewicz, D. A.; Krizus, A.; Han, F. Y.; Ceballos-Picot,
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96. Rosen, D. R.; Siddique, T.; Patterson, D.; Figlewicz, D. A.; Sapp,
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101. Sato, T.; Nakanishi, T.; Yamamoto, Y.; Andersen, P. M.; Ogawa,
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102. Scott-Emuakpor, A. B.; Heffelfinger, J.; Higgins, J. V.: A syndrome
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103. Shibata, N.; Hirano, A.; Kobayashi, M.; Sasaki, S.; Kato, T.;
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110. Siddique, T.; Pericak-Vance, M. A.; Caliendo, J.; Hong, S.-T.;
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111. Simpson, C. L.; Lemmens, R.; Miskiewicz, K.; Broom, W. J.; Hansen,
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112. Storkebaum, E.; Lambrechts, D.; Dewerchin, M.; Moreno-Murciano,
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113. Swerts, L.; Van den Bergh, R.: Sclerose laterale amyotrophique
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117. Tateno, M.; Sadakata, H.; Tanaka, M.; Itohara, S.; Shin, R.-M.;
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Molec. Genet. 19: 2284-2302, 2010.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive

MUSCLE, SOFT TISSUE:
Muscle weakness and atrophy;
Fasciculations;
Muscle cramps

NEUROLOGIC:
[Central nervous system];
Spasticity;
Hyperreflexia;
Ocular motility spared;
Upper and lower neuron manifestations;
Bulbar dysfunction (e.g. dysarthria and dysphagia);
Sleep apnea;
Pseudobulbar palsy (e.g. involuntary weeping or laughter);
Pathologic changes in anterior horn cells and lateral corticospinal
tracts

LABORATORY ABNORMALITIES:
Reduced cytosolic superoxide dismutase-1 (SOD1)

MISCELLANEOUS:
Approximately 10% of ALS cases are familial;
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the superoxide dismutase-1 gene (SOD-1, 147450.0001)
Susceptibility conferred by mutation in the angiogenin gene (ANG,
105850.0001);
Susceptibility conferred by mutation in the neurofilament, heavy polypeptide
gene (NEFH, 162230.0001);
Susceptibility conferred by mutation in the peripherin gene (PRPH,
170710.0001);
Susceptibility conferred by mutation in the dynactin 1 gene (DCTN1,
601143.0002)

*FIELD* CN
Joanna S. Amberger - updated: 5/2/2006
Ada Hamosh - reviewed: 4/14/2000
Kelly A. Przylepa - revised: 2/21/2000

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

*FIELD* ED
joanna: 07/02/2013
joanna: 7/2/2013
joanna: 10/5/2012
joanna: 5/2/2006
joanna: 1/30/2002
joanna: 8/9/2001
joanna: 4/14/2000
kayiaros: 2/21/2000

*FIELD* CN
George E. Tiller - updated: 8/20/2013
Cassandra L. Kniffin - updated: 2/27/2013
Ada Hamosh - updated: 2/1/2013
Cassandra L. Kniffin - updated: 10/1/2012
Cassandra L. Kniffin - updated: 5/5/2011
Cassandra L. Kniffin - updated: 1/28/2011
George E. Tiller - updated: 12/29/2010
Ada Hamosh - updated: 10/19/2010
Cassandra L. Kniffin - updated: 9/27/2010
George E. Tiller - updated: 8/6/2010
Ada Hamosh - updated: 6/18/2010
Cassandra L. Kniffin - updated: 6/14/2010
Ada Hamosh - updated: 6/2/2010
Ada Hamosh - updated: 1/19/2010
Cassandra L. Kniffin - updated: 12/29/2009
Cassandra L. Kniffin - updated: 12/15/2009
George E. Tiller - updated: 8/14/2009
George E. Tiller - updated: 8/12/2009
Cassandra L. Kniffin - updated: 6/22/2009
Cassandra L. Kniffin - updated: 1/14/2009
Ada Hamosh - updated: 9/24/2008
Cassandra L. Kniffin - updated: 8/13/2008
Victor A. McKusick - updated: 5/28/2008
Ada Hamosh - updated: 5/8/2008
Cassandra L. Kniffin - updated: 3/14/2008
Patricia A. Hartz - updated: 3/3/2008
Cassandra L. Kniffin - updated: 1/7/2008
Cassandra L. Kniffin - updated: 9/17/2007
Cassandra L. Kniffin - updated: 8/28/2007
Cassandra L. Kniffin - updated: 4/12/2007
George E. Tiller - updated: 4/5/2007
Cassandra L. Kniffin - updated: 3/29/2007
Ada Hamosh - updated: 10/25/2006
Ada Hamosh - updated: 7/24/2006
Cassandra L. Kniffin - reorganized: 6/20/2006
Cassandra L. Kniffin - updated: 6/14/2006
Cassandra L. Kniffin - updated: 5/25/2006
Victor A. McKusick - updated: 4/27/2006
Cassandra L. Kniffin - updated: 4/20/2006
Cassandra L. Kniffin - updated: 11/2/2005
Cassandra L. Kniffin - updated: 8/19/2005
Cassandra L. Kniffin - updated: 6/9/2005
Cassandra L. Kniffin - updated: 3/4/2005
Cassandra L. Kniffin - updated: 2/14/2005
Victor A. McKusick - updated: 12/14/2004
Cassandra L. Kniffin - updated: 12/14/2004
Ada Hamosh - updated: 6/11/2004
Victor A. McKusick - updated: 4/29/2004
Ada Hamosh - updated: 3/8/2004
Ada Hamosh - updated: 9/17/2003
Cassandra L. Kniffin - updated: 6/9/2003
Cassandra L. Kniffin - updated: 2/19/2003
Dawn Watkins-Chow - updated: 11/22/2002
Dawn Watkins-Chow - updated: 11/5/2002
Victor A. McKusick - updated: 10/1/2002
Cassandra L. Kniffin - updated: 7/23/2002
George E. Tiller - updated: 1/30/2002
Victor A. McKusick - updated: 6/25/2001
Ada Hamosh - updated: 4/13/2000
Victor A. McKusick - updated: 3/9/1999
Orest Hurko - updated: 1/21/1999
Victor A. McKusick - updated: 10/2/1998
Victor A. McKusick - updated: 5/6/1998
Orest Hurko - updated: 5/8/1996

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
carol: 11/06/2013
ckniffin: 11/6/2013
carol: 11/5/2013
carol: 10/1/2013
alopez: 9/24/2013
carol: 9/17/2013
tpirozzi: 9/10/2013
tpirozzi: 8/28/2013
tpirozzi: 8/27/2013
tpirozzi: 8/21/2013
tpirozzi: 8/20/2013
terry: 4/4/2013
carol: 3/7/2013
ckniffin: 2/27/2013
alopez: 2/7/2013
terry: 2/1/2013
carol: 10/16/2012
carol: 10/8/2012
ckniffin: 10/1/2012
terry: 9/14/2012
carol: 9/6/2012
alopez: 9/6/2012
carol: 7/10/2012
ckniffin: 7/2/2012
terry: 6/6/2012
carol: 12/8/2011
ckniffin: 12/8/2011
carol: 10/4/2011
alopez: 9/23/2011
terry: 6/3/2011
wwang: 5/18/2011
ckniffin: 5/5/2011
wwang: 2/18/2011
ckniffin: 1/28/2011
wwang: 1/12/2011
terry: 12/29/2010
alopez: 10/19/2010
wwang: 9/29/2010
ckniffin: 9/27/2010
alopez: 9/21/2010
terry: 9/14/2010
wwang: 8/12/2010
terry: 8/6/2010
alopez: 6/21/2010
terry: 6/18/2010
wwang: 6/18/2010
ckniffin: 6/14/2010
alopez: 6/8/2010
terry: 6/2/2010
alopez: 1/19/2010
wwang: 1/13/2010
ckniffin: 12/29/2009
carol: 12/23/2009
ckniffin: 12/15/2009
wwang: 9/1/2009
ckniffin: 9/1/2009
wwang: 8/31/2009
wwang: 8/25/2009
terry: 8/12/2009
wwang: 7/21/2009
ckniffin: 6/22/2009
wwang: 3/3/2009
wwang: 1/16/2009
ckniffin: 1/14/2009
wwang: 10/6/2008
alopez: 9/24/2008
terry: 9/24/2008
wwang: 8/19/2008
ckniffin: 8/13/2008
alopez: 5/29/2008
terry: 5/28/2008
alopez: 5/21/2008
terry: 5/8/2008
wwang: 4/1/2008
ckniffin: 3/14/2008
mgross: 3/3/2008
wwang: 1/18/2008
ckniffin: 1/7/2008
alopez: 1/3/2008
ckniffin: 11/13/2007
wwang: 9/24/2007
ckniffin: 9/17/2007
wwang: 9/4/2007
ckniffin: 8/28/2007
wwang: 4/19/2007
ckniffin: 4/12/2007
alopez: 4/11/2007
terry: 4/5/2007
wwang: 3/30/2007
ckniffin: 3/29/2007
alopez: 11/2/2006
terry: 10/25/2006
alopez: 7/28/2006
terry: 7/24/2006
carol: 7/19/2006
ckniffin: 7/17/2006
ckniffin: 6/26/2006
terry: 6/21/2006
carol: 6/20/2006
ckniffin: 6/14/2006
wwang: 6/2/2006
ckniffin: 5/25/2006
joanna: 5/2/2006
alopez: 5/2/2006
terry: 4/27/2006
wwang: 4/25/2006
ckniffin: 4/20/2006
ckniffin: 3/13/2006
wwang: 11/11/2005
ckniffin: 11/2/2005
alopez: 10/20/2005
terry: 10/12/2005
terry: 9/12/2005
wwang: 8/26/2005
ckniffin: 8/19/2005
wwang: 6/15/2005
ckniffin: 6/9/2005
wwang: 3/16/2005
ckniffin: 3/4/2005
wwang: 2/23/2005
ckniffin: 2/14/2005
carol: 12/22/2004
ckniffin: 12/14/2004
alopez: 10/25/2004
alopez: 6/15/2004
terry: 6/11/2004
tkritzer: 4/30/2004
terry: 4/29/2004
tkritzer: 3/9/2004
terry: 3/8/2004
alopez: 9/17/2003
mgross: 8/12/2003
carol: 6/12/2003
ckniffin: 6/9/2003
carol: 2/24/2003
ckniffin: 2/19/2003
mgross: 11/22/2002
carol: 11/7/2002
tkritzer: 11/7/2002
carol: 11/7/2002
tkritzer: 11/5/2002
tkritzer: 10/2/2002
tkritzer: 10/1/2002
carol: 8/9/2002
tkritzer: 8/9/2002
ckniffin: 7/23/2002
cwells: 2/6/2002
cwells: 1/30/2002
terry: 6/25/2001
alopez: 4/13/2000
terry: 4/13/2000
terry: 4/30/1999
carol: 3/23/1999
terry: 3/9/1999
carol: 3/7/1999
carol: 1/21/1999
dkim: 11/6/1998
carol: 10/7/1998
terry: 10/2/1998
carol: 5/11/1998
terry: 5/6/1998
alopez: 5/5/1998
joanna: 12/15/1997
jenny: 11/5/1997
mark: 5/14/1997
mark: 3/12/1997
mark: 1/29/1997
jenny: 12/23/1996
terry: 12/18/1996
terry: 5/10/1996
mark: 5/8/1996
terry: 5/3/1996
mark: 2/22/1996
mark: 1/31/1996
terry: 1/26/1996
mark: 3/29/1995
davew: 8/16/1994
carol: 6/8/1994
warfield: 4/21/1994
mimadm: 4/14/1994
pfoster: 3/25/1994

MIM 147450
*RECORD*
*FIELD* NO
147450
*FIELD* TI
*147450 SUPEROXIDE DISMUTASE 1; SOD1
;;SUPEROXIDE DISMUTASE, CYTOSOLIC;;
SUPEROXIDE DISMUTASE, SOLUBLE;;
read moreSOD, SOLUBLE;;
SUPEROXIDE DISMUTASE, COPPER-ZINC;;
INDOPHENOL OXIDASE A; IPOA
*FIELD* TX

DESCRIPTION

The SOD1 gene encodes superoxide dismutase-1 (EC 1.15.1.1), a major
cytoplasmic antioxidant enzyme that metabolizes superoxide radicals to
molecular oxygen and hydrogen peroxide, thus providing a defense against
oxygen toxicity (Niwa et al., 2007). Soluble cytoplasmic SOD1 is a
copper- and zinc-containing enzyme; the SOD1 gene maps to chromosome
21q22 (Sherman et al., 1983). SOD2 (147460) is a distinct mitochondrial
enzyme that contains manganese; the SOD2 gene maps to 6q25. SOD1 is a
homodimer and SOD2 a tetramer (Beckman et al., 1973).

Fridovich (1979) concluded that SOD1 and SOD2 evolved from different
primordial genes, which is an example of analogy, not homology, and of
convergent evolution. Doonan et al. (1984) cited the superoxide
dismutases as an example of cytosolic and mitochondrial isoenzymes with
no apparent evolutionary relationship.

CLONING

Barra et al. (1980) and Jabusch et al. (1980) independently determined
the amino acid structure of human superoxide dismutase-1. The
153-residue protein shares approximately 82% homology with the bovine
protein.

Sherman et al. (1983) isolated clones corresponding to the human SOD1
gene. The deduced 153-residue protein has a calculated molecular mass of
approximately 18.5 kD. Two mRNA transcripts of 0.5 and 0.7 kb were
detected. Both mRNAs encoded the same protein, which had functional
activity in vitro.

By RT-PCR analysis, Hirano et al. (2000) identified 5 splice variants of
SOD1. The variants were expressed in a tissue-specific manner, including
expression in brain, a region involved in amyotrophic lateral sclerosis
(ALS; 105400). Hirano et al. (2000) designated the variants, which were
found in both ALS patients and controls, LP1 (lacking part of exon 1),
LP1P2 (lacking part of exon 1 and part of exon 2), LE2 (lacking entire
exon 2), LE2E3 (lacking entire exons 2 and 3), and LP1E2E3 (lacking part
of exon 1 and entire exons 2 and 3).

Green et al. (2002) sequenced, characterized, and mapped the canine SOD1
gene. The deduced canine SOD1 protein contains 153 amino acids and
shares more than 79% sequence identity with mammalian homologs.

MAPPING

By mouse-man somatic cell hybridization, Tan et al. (1973) mapped the
SOD1 gene to chromosome 21.

Lin et al. (1980) demonstrated that the genes for soluble Sod1 and
interferon sensitivity are syntenic in the mouse and located on mouse
chromosome 16, which is homologous to part of human chromosome 21.

In the mouse, Novak et al. (1980) showed that a locus affecting SOD1
activity was closely linked to the H-2 cluster, suggesting that the
locus may be regulatory in nature.

Wulfsberg et al. (1983) found normal levels of SOD1 in a patient with an
interstitial deletion of chromosome 21 leading to monosomy for band q21.
They concluded that the gene for SOD1 is located at 21q22.1.

Huret et al. (1987) used in situ hybridization on metaphase chromosomes
to confirm SOD1 gene localization in the segment enclosing the distal
part of chromosome 21q21 and 21q22.1.

Green et al. (2002) mapped the canine Sod1 gene to chromosome 31 close
to syntenic group 13 on the radiation hybrid map in the vicinity of the
sodium/myoinositol transporter (SMIT) gene (SLC5A3; 600444).

- SOD1 Dosage Effect in Trisomy 21 (Down Syndrome)

Sichitiu et al. (1974) noted that the fact that SOD1 was elevated in
trisomy 21, or Down syndrome (190685), added support to the location of
the gene on chromosome 21.

Feaster et al. (1977) demonstrated dosage effects of SOD1 in nucleated
lymphocytes and polymorphonuclear cells from persons with trisomy 21 and
monosomy 21. Earlier studies had been done with anucleated erythrocytes
and platelets. Kedziora et al. (1979) cast some doubt on the
significance of excessive SOD1 in the Down syndrome phenotype, because
SOD1 levels were normal in 3 patients with Down syndrome due to
translocations.

Nakai et al. (1984) extended the observations on SOD1 dosage effect in
aneuploid cells: a case of monosomy 21 showed half normal levels of
enzyme.

Brooksbank and Balazs (1983) showed that SOD1 activity in trisomy 21
fetal brain was enhanced while glutathione peroxidase (see, e.g., GPX1,
138320) activity, which would have a compensating effect, was not.
Cerebral cortex tissue from a patient with Down syndrome showed
increased lipoperoxidation compared to controls. The authors suggested
that increased SOD1 activity could result in an abnormally high
concentration of hydrogen peroxide in nerve cells, which may cause free
radical damage to cell membrane lipids and play a pathogenetic role in
Down syndrome.

Huret et al. (1987) studied an 18-month-old boy with many typical Down
syndrome features but a normal cytogenetic analysis. However, SOD1 was
increased in the patient's red cells as in trisomy 21, and Southern blot
analysis demonstrated that the patient had 3 SOD1 genes. In situ
hybridization on metaphase chromosomes with the same probe confirmed the
gene localization in the segment enclosing the distal part of chromosome
21q21 and 21q22.1. Huret et al. (1987) concluded were that the Down
syndrome phenotype of this patient was due to microduplication of a
segment of chromosome 21.

In a family with clinical features of Down syndrome caused by
submicroscopic duplication of distal band q22.1 in addition to bands
q22.2 and q22.3 of chromosome 21, Korenberg et al. (1990) found that the
SOD1 and APP (104760) genes did not play a necessary role in generating
the classic Down syndrome features.

Ackerman et al. (1988) described a young child with partial monosomy 21
in whom pulmonary oxygen toxicity occurred due presumably to deficiency
of SOD1. The child underwent 2 operative procedures with different
anesthetic techniques, which resulted in exposure to low concentrations
of inspired oxygen during the first procedure and exposure to high
concentrations during the second. Signs of pulmonary oxygen toxicity
developed only after exposure to the high concentration. Blood samples
obtained on 3 separate occasions showed levels of SOD1 that were 40% of
those in controls.

Minc-Golomb et al. (1991) suggested that overexpression of the SOD1 gene
is responsible for alteration in prostaglandin biosynthesis in trisomy
21 cells.

GENE FUNCTION

McCord and Fridovich (1969) demonstrated that superoxide dismutase
catalyzes the oxidation/reduction conversion of superoxide radicals to
molecular oxygen and hydrogen peroxide. The name 'superoxide dismutase'
comes from the fact that the reaction is a 'dismutation' of superoxide
anions. The protein had been known for over 30 years as a
copper-containing, low molecular weight cytoplasmic protein identified
in erythrocytes, referred to as 'erythrocuprein' or 'hemocuprein.' See
review of Fridovich (1975).

Richardson et al. (1976) noted the similarity between the 3-dimensional
protein structures of immunoglobulins and individual Cu-Zn SOD1
subunits.

Keller et al. (1991) concluded that SOD1 is a peroxisomal enzyme. On
immunofluorescence using 4 monoclonal antibodies, SOD1 colocalized with
catalase (CAT; 115500) in human fibroblasts and hepatoma cells. In
fibroblasts from patients with Zellweger syndrome (see 214100), in which
there are peroxisomal defects, SOD1 was not transported to the
peroxisomal ghosts, but, like catalase, remained in the cytoplasm. A
study of yeast cells expressing human SOD1 showed that the enzyme is
translocated to peroxisomes. Crapo et al. (1992), however, concluded
that SOD1 is widely distributed in the cell cytosol and in the cell
nucleus, consistent with its being a soluble cytosolic protein.
Mitochondria and secretory compartments did not label with the
antibodies they used. In human cells, peroxisomes showed a labeling
density slightly less than that of cytoplasm.

Using immunohistochemistry, Pardo et al. (1995) demonstrated SOD1 in
motor neurons, interneurons, and sensory neurons of mouse and human
spinal cord. SOD1 was distributed in a punctate pattern throughout
neuronal perikarya, in proximal dendrites, and in terminal axons. In the
brain, SOD1 was present in motor and sensory cranial nerve nuclei, as
well as diffusely through the brain in the neurons of the cortex,
certain regions of the hippocampus, and amygdala. The intracellular
localization was primarily cytoplasmic, but also included nuclei and
membranous organelles, presumably peroxisomes. Due to the diffuse and
abundant SOD1 expression, Pardo et al. (1995) concluded that pathogenic
SOD1 mutations result in a toxic gain of adverse function rather than
haploinsufficiency.

Huang et al. (2000) reported that certain estrogen derivatives
selectively kill human leukemia cells but not normal lymphocytes. Using
cDNA microarray and biochemical approaches, Huang et al. (2000)
identified SOD1 as a target of this drug action and showed that chemical
modifications at the 2-carbon (2-OH, 2-OCH3) of the estrogen derivatives
are essential for SOD inhibition and for induction of apoptosis.
Inhibition of SOD causes accumulation of cellular superoxide radical and
leads to free radical-mediated damage to mitochondrial membranes, the
release of cytochrome c from mitochondria, and apoptosis of the cancer
cells. Huang et al. (2000) concluded that targeting SOD1 may be a
promising approach to the selective killing of cancer cells and that
mechanism-based combinations of SOD inhibitors with free
radical-producing agents may have clinical applications.

Growth factor signaling elicits an increase in reactive oxygen species,
which inactivates protein tyrosine phosphatases (PTPs; see 176876) by
oxidizing an active-site cysteine, shifting the balance within cells
toward phosphorylation and allowing kinase cascades to propagate. Juarez
et al. (2008) showed that chemical inhibition of SOD1 in human tumor and
endothelial cells prevented formation of sufficiently high levels of
H2O2, resulting in protection of PTPs from H2O2-mediated inactivation.
This, in turn, led to inhibition of EGF (131530)-, IGF1 (147440)-, and
FGF2 (134920)-mediated phosphorylation of ERK1 (MAPK3; 601795)/ERK2
(MAPK1; 176948) and caused downregulation of PDGF receptor (PDGFRB;
173410). SOD1 inhibition increased the steady-state levels of
superoxide, which induced protein oxidation in A431 human tumor cells
but spared phosphatases. Thus, SOD1 inhibition in A431 cells resulted in
both prooxidant effects caused by increased superoxide levels and
antioxidant effects caused by reduced H2O2 levels. Juarez et al. (2008)
concluded that SOD1 plays an essential role in growth factor-mediated
MAPK signaling by mediating transient oxidation and inactivation of
PTPs.

MOLECULAR GENETICS

DeCroo et al. (1988) reported an isoelectric focusing technique to look
for SOD1 heterogeneity in erythrocytes.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

- Amyotrophic Lateral Sclerosis 1

In patients from 13 different families with amyotrophic lateral
sclerosis (ALS; 105400), Rosen et al. (1993) identified 11 different
heterozygous mutations in the SOD1 gene (147450.0001-147450.0011). The
authors presented 2 possible mechanisms by which mutations in SOD1 could
cause the disorder: decreased SOD1 activity leading to the accumulation
of toxic superoxide radicals, or increased SOD1 activity leading to
excessive levels of hydrogen peroxide and a highly toxic hydroxyl
radical, which can be formed through the reaction of hydrogen peroxide
with a transition metal such as iron. Increased SOD1 activity may result
in a dominant-negative effect.

In a complete screening of the SOD1 coding region in 25 families with
ALS, Deng et al. (1993) found that the A4V (147450.0012) substitution in
exon 1 was the most frequent, occurring in 8 families. Other mutations
were identified in exons 2, 4, and 5, but not in the active site region
formed by exon 3. Examination of the crystal structure of human SOD1
established that all 12 observed sites of mutation causing ALS alter
conserved interactions critical to the beta-barrel fold and dimer
contact, rather than catalysis. Red cells from heterozygotes had less
than 50% normal SOD activity, consistent with a structurally defective
SOD dimer.

In a review of familial amyotrophic lateral sclerosis, de Belleroche et
al. (1995) cataloged 30 missense mutations and a 2-bp deletion in the
SOD1 gene.

Orrel et al. (1997) described a mutation in exon 3 of the SOD1 gene
(147450.0028) associated with familial ALS. Previously, more than 50
different mutations had been described involving exons 1, 2, 4, and 5.

Cudkowicz et al. (1997) registered 366 families in a study of dominantly
inherited ALS. They screened 290 families for mutations in the SOD1 gene
and detected mutations in 68 families. The A4V mutation was the most
common, occurring in 50% of families.

Andersen et al. (1995) identified a homozygous mutation in the SOD1 gene
(D90A; 147450.0015) in 14 affected individuals from 4 unrelated Swedish
or Finnish families with ALS. Several of the families were
consanguineous, indicating autosomal recessive inheritance. In a
worldwide haplotype study of 28 pedigrees with the D90A mutation,
Al-Chalabi et al. (1998) found that 20 recessive families shared the
same founder haplotype, regardless of geographic location, whereas
several founders existed for the 8 dominant families. The findings
confirmed that D90A can act in a dominant fashion in keeping with all
other SOD1 mutations, but that on one occasion, a new instance of this
mutation was recessive. Al-Chalabi et al. (1998) proposed that a tightly
linked protective factor modifies the toxic effect of mutant SOD1 in
recessive families.

In 2 sibs with ALS, Hand et al. (2001) identified compound
heterozygosity in the SOD1 gene: D90A (147450.0015) and D96N
(147450.0032), indicating autosomal recessive inheritance.

Aguirre et al. (1999) used a nonradioactive SSCP method, in combination
with solid phase sequencing, to screen the entire SOD1 coding region and
flanking intronic sequences for mutations in 23 patients from 11 ALS
families and 69 patients with sporadic ALS, all of Belgian origin. In 7
families, 3 different mutations were identified: L38V (147450.0002),
D90A, and G93C (147450.0007). The D90A mutation was found only in
heterozygous state, in 2 families and in 1 apparently sporadic case.

Among 233 patients with sporadic ALS, Broom et al. (2004) found no
association between disease susceptibility or phenotype and a deletion
and 4 SNPs spanning the SOD1 gene, or their combined haplotypes, arguing
against a major role for wildtype SOD1 in sporadic ALS.

Sato et al. (2005) measured the ratio of mutant-to-normal SOD1 protein
in 29 ALS patients with mutations in the SOD1 gene. Although there was
no relation to age at onset, turnover of mutant SOD1 was correlated with
a shorter disease survival time.

Millecamps et al. (2010) identified 18 different SOD1 missense mutations
in 20 (12.3%) of 162 French probands with familial ALS. Compared to
those with ALS caused by mutations in other genes, those with SOD1
tended to have predominantly lower limb onset. One-third of SOD1
patients survived for more than 7 years: these patients had an earlier
disease onset compared to those presenting with a more rapid course. No
patients with SOD1 mutations developed cognitive impairment.

- Studies on Mutant SOD1 Proteins

Lyons et al. (1996) observed that replacement of zinc ion in the zinc
sites of mutant SOD1 proteins with either copper ion or cobalt ion
yielded metal-substituted derivatives with spectroscopic properties
different from those of the analogous derivative of the wildtype
proteins. The findings indicated that the geometries of binding of these
metal ions to the zinc site were affected by the mutations. Several of
the ALS-associated mutant copper-zinc oxide dismutases were also found
to be reduced by ascorbate at significantly greater rates than the
wildtype proteins. Lyons et al. (1996) concluded that similar
alterations in the properties of the zinc binding site can be caused by
mutations scattered throughout the protein structure.

Estevez et al. (1999) observed that the loss of zinc from either
wildtype or ALS-mutant SOD was sufficient to induce apoptosis in
cultured motor neurons. Toxicity required that copper be bound to SOD
and depended on endogenous production of nitric oxide. When replete with
zinc, neither ALS-mutant nor wildtype Cu,Zn SODs were toxic, and both
protected motor neurons from trophic factor withdrawal. Estevez et al.
(1999) concluded that zinc-deficient SOD may participate in both
sporadic and familial ALS by an oxidative mechanism involving nitric
oxide.

Okado-Matsumoto and Fridovich (2002) demonstrated that the entry of SOD1
into mitochondria depends on demetallation and that heat shock proteins
block the uptake of familial ALS-associated mutant SOD1, while having no
effect on wildtype SOD1. The binding of mutant SOD1 to heat shock
proteins in the extract of neuroblastoma cells leads to formation of
sedimentable aggregates. The authors suggested that this binding of heat
shock proteins to mutant forms of a protein abundant in motor neurons,
such as SOD1, makes heat shock proteins unavailable for their proper
antiapoptotic functions and ultimately leads to motor neuron death. The
hypothesis could explain a mechanism of a toxic gain of function.

Lindberg et al. (2002) looked for folding-related defects by comparing
the unfolding behavior of 5 SOD1 mutants with distinct structural
characteristics: A4V (147450.0012) at the interface between the N and C
termini, C6F (147450.0020) in the hydrophobic core, D90A (147450.0015)
at the protein surface, and G93A (147450.0008) and G93C (147450.0007),
which decrease backbone flexibility. With the exception of the
disruptive replacements A4V and C6F, the mutations only marginally
affected the stability of the native protein, yet all shared a
pronounced destabilization of the metal-free apoprotein state: the
higher the stability loss, the lower the mean survival time for ALS
patients carrying the mutation. Thus, organism-level pathology may be
directly related to the properties of the immature state of a protein
rather than to those of the native species.

Valentine and Hart (2003) reviewed the 2 hypotheses that had dominated
discussion of the toxicity of mutant SOD1 proteins: the oligomerization
and oxidative damage hypotheses. The oligomerization hypothesis
maintained that mutant SOD1 proteins are, or become, misfolded and
consequently oligomerize into increasingly high molecular mass species
that ultimately lead to the death of motor neurons. The oxidative damage
hypothesis maintained that mutant SOD1 proteins catalyze oxidative
reactions that damage substrates critical for viability of the altered
cells. Valentine and Hart (2003) reviewed some of the properties of both
wildtype and mutant SOD1 proteins and suggested how these properties may
be relevant to the 2 hypotheses, which they proposed were not
necessarily mutually exclusive.

Stathopulos et al. (2003) reported that purified SOD formed aggregates
in vitro under destabilizing solution conditions by a process involving
a transition from small amorphous species to fibrils. The assembly
process and the tinctorial and structural properties of the in vitro
aggregates resembled those for aggregates observed in vivo. Furthermore,
Stathopulos et al. (2003) found that the familial ALS SOD1 mutations A4V
(147450.0012), E100G (147450.0009), G93A (147450.0008), and G93R
(147450.0033) decreased protein stability, which correlated with an
increase in the propensity of the mutants to form aggregates. These
mutations also increase the rate of protein unfolding. The data
supported the hypothesis that the toxic gain of function for many
different familial ALS-associated mutant SODs is a consequence of
protein destabilization, which leads to an increase in the formation of
cytotoxic protein aggregates.

Hough et al. (2004) stated that more than 90 point mutations in the SOD1
gene had been found to lead to the development of familial ALS. They
pointed to evidence suggesting that a subset of mutations located close
to the dimeric interface can lead to a major destabilization of the
mutant enzymes.

Hough et al. (2004) determined the crystal structure of the A4V
(147450.0012) and I113T (147450.0011) mutants to 1.9 and 1.6 angstroms,
respectively. In the A4V structure, small changes at the dimer interface
result in a substantial reorientation of the 2 monomers. This effect was
also seen in the case of the I113T crystal structure, but to a smaller
extent. X-ray solution scattering data showed that in the solution
state, both of the mutants undergo a more pronounced conformational
change compared with wildtype superoxide dismutase than was observed in
the A4V crystal structure. The results demonstrated that the A4V and
I113T mutants are substantially destabilized in comparison with wildtype
SOD1. Commenting on the work of Hough et al. (2004), Ray and Lansbury
(2004) raised the possibility of therapeutic measures to stabilize the
SOD1 dimer. The general strategy of inhibiting potentially pathogenic
aggregation by stabilizing native oligomers was first proposed and
accomplished by Koo et al. (1999) in connection with another
aggregation-dependent degenerative disease, familial amyloid
polyneuropathy, which is caused by point mutation in the gene encoding
transthyretin (TTR; 176300).

Miyazaki et al. (2004) found that NEDL1 (HECW1; 610384), a neuronal
ubiquitin-protein ligase, bound translocon-associated protein-delta
(TRAPD, or SSR4; 300090) and also bound and ubiquitinated mutant SOD1,
but not wildtype SOD1. The strength of the interaction between NEDL1 and
mutant SOD1 was proportional to the severity of the SOD1 mutation. NEDL1
associated with mutant SOD1 and ubiquitin in Lewy body-like hyaline
inclusions in ventral horn motor neurons of familial ALS patients and
mutant Sod1 transgenic mice. Yeast 2-hybrid screening identified
dishevelled-1 (DVL1; 601365), a key transducer in the WNT (see WNT1,
164820) signaling pathway, as a physiologic substrate for NEDL1. Mutant
SOD1 interacted with DVL1 in the presence of NEDL1 and caused DVL1
dysfunction.

Rodriguez et al. (2005) used differential scanning calorimetry and
hydrogen-deuterium (H/D) exchange, followed by mass spectrometric
analysis, to compare ALS-associated SOD1 mutants with wildtype SOD1.
They found that the mutant proteins were not universally destabilized,
and that several mutants had normal metallation properties and resembled
the wildtype protein in terms of thermal stability and H/D kinetics.
Rodriguez et al. (2005) concluded that the causes of SOD1-linked ALS are
complex and are not simply related to apoprotein stability, although
destabilization may contribute to the toxicity of some ALS-associated
SOD1 mutants.

Harraz et al. (2008) demonstrated that SOD1 directly regulated cellular
NOX2 (300481) production of reactive oxygen species by binding RAC1
(602048) and inhibiting RAC1 GTPase activity. Oxidation of RAC1
uncoupled SOD1 binding in a reversible fashion, suggesting a model of
redox sensing. ALS-associated mutant SOD1 lacked the redox sensitivity,
resulting in enhanced RAC1/NOX1 activation and increased production of
reactive oxygen species in neuronal and glial cells, leading to cell
death. Glial cell toxicity in cell culture was attenuated by apocynin, a
NOX inhibitor, and ALS mice treated with apocynin showed increased life
span. Harraz et al. (2008) concluded that certain SOD1 mutations exert a
dominant-negative effect by interfering with normal SOD1/RAC1
interactions. The results also showed that SOD1 can act as a regulatory
molecule in addition to its role as a catabolic enzyme.

Using buoyant-density centrifugation and protease studies, Vande Velde
et al. (2008) demonstrated that mutant misfolded SOD1, particularly
dismutase-inactive SOD1, was bound to cytoplasmic outer mitochondrial
membranes in an alkali- and salt-resistant manner. Mutant SOD1 binding
was selective for mitochondrial membranes and restricted to spinal cord
tissue. Vande Velde et al. (2008) postulated that exposure to
mitochondria of misfolded mutant SOD1 conformers could be mediated by
tissue-selective cytoplasmic chaperones, components on the cytoplasmic
face of spinal mitochondria, or misfolded SOD1 conformers unique to
spinal cord and with an affinity for mitochondrial membranes.

Using mouse motor neurons and human embryonic kidney cells expressing
SOD1 proteins with ALS-associated mutations (e.g., G93A), Nishitoh et
al. (2008) showed that mutant SOD1 interacted with the C-terminal
cytoplasmic region of DERL1 (608813), a component of the endoplasmic
reticulum (ER)-associated degradation (ERAD) machinery, and triggered ER
stress through ERAD dysfunction. Mutant SOD1 induced formation of an
Ire1 (ERN1; 604033)-Traf2 (601895)-Ask1 (MAP3K5; 602448) complex on the
ER membrane of mouse motor neurons and activated Ask1 by triggering ER
stress-induced Ire1 activation. Dissociation of mutant SOD1 from Derl1
protected motor neurons from mutant SOD1-induced cell death.
Furthermore, deletion of Ask1 partially mitigated motor neuron loss in
vitro and extended the life span of SOD1-mutant transgenic mice.
Nishitoh et al. (2008) concluded that interaction of mutant SOD1 with
DERL1 is crucial for disease progression in familial ALS.

Prudencio et al. (2009) used a large set of data from SOD1-associated
ALS pedigrees to identify correlations between disease features and
biochemical/biophysical properties of more than 30 different SOD1
mutations. All ALS-associated SOD1 mutations tested increased the
inherent aggregation propensity of the protein with considerable
variation in relative aggregation propensity between mutations.
Variation in aggregation rates was not influenced by differences in
known protein properties such as enzyme activity, protein
thermostability, mutation position, or degree of change in protein
charge. However, the majority of pedigrees in which patients exhibited
reproducibly short disease durations were associated with mutations that
showed a high inherent propensity to induce SOD1 aggregation.

Magrane et al. (2009) generated NSC34 murine motor neuronal cells
expressing wildtype or mutant SOD1 containing a cleavable intermembrane
space (IMS) targeting signal to directly investigate the pathogenic role
of mutant SOD1 in mitochondria. Mitochondrially-targeted SOD1 localized
to the IMS, where it was enzymatically active. Mutant IMS-targeted SOD1
caused neuronal toxicity under metabolic and oxidative stress
conditions. Motor neurons expressing IMS-mutant SOD1 demonstrated
neurite mitochondrial fragmentation and impaired mitochondrial dynamics.
These defects were associated with impaired maintenance of neuritic
processes. Magrane et al. (2009) concluded that mutant SOD1 localized in
the IMS is sufficient to cause mitochondrial abnormalities and neuronal
toxicity and contributes to ALS pathogenesis.

Pedrini et al. (2010) showed that the toxicity of mutant SOD1 relies on
its spinal cord mitochondria-specific interaction with BCL2 (151430).
Mutant SOD1 induced morphologic changes and compromised mitochondrial
membrane integrity leading to the release of cytochrome c only in the
presence of BCL2. In cells and in mouse and human spinal cord
homogenates with SOD1 mutations, binding to mutant SOD1 triggered a
conformational change in BCL2 that resulted in the exposure of its BH3
domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain
failed to support mutant SOD1-mediated mitochondrial toxicity.

- Associations Pending Confirmation

For discussion of a possible association between variation in the SOD1
gene and keratoconus, see KTCN1 (148300).

HISTORY

Brewer (1967) identified superoxide dismutase as an indophenol oxidase
by protein analysis of starch gels using the phenazine-tetrazolium
technique. In addition to the appearance of blue bands marking the site
of the isozymes under investigation, there were light or achromatic
areas resulting from a protein that oxidized tetrazolium dyes in the
presence of phenazine and light. Brewer (1967) detected this enzyme in
several human tissues and referred to it as 'indophenol oxidase A'
(IPO-A).

Brewer (1967) observed an electrophoretic variant of IPO-A, which he
called 'Morenci,' in 3 generations of a family with presumed
male-to-male transmission. Baur (cited by Baur and Schorr, 1969)
observed an electrophoretic variant of tetrazolium oxidase in a
Caucasian mother and 1 of 2 children. Welch and Mears (1972) found an
unusually high frequency of a variant in one of the Orkney Islands.
Beckman (1973) reported on the frequency of the 'Morenci' SOD1 enzyme
variant in a population of northern Sweden.

ANIMAL MODEL

Baur and Schorr (1969) reported a genetic polymorphism of red cell
tetrazolium oxidase (Sod1) in the dog.

Epstein et al. (1987) created transgenic mice with increased activity of
Sod1 and proposed this as a useful model for investigating the effects
of increased SOD1 in Down syndrome.

- Animal Models of Amyotrophic Lateral Sclerosis

Gurney et al. (1994) showed that overexpression of Sod1 in transgenic
mice led to an apparently specific defect in distal motor neuron
terminals of the tongue and hindlimbs, indicating that this gene
selectively affects motor neurons.

In cultured rat lumbar spinal cord slices, Rothstein et al. (1994)
observed that chronic inhibition of Sod1 resulted in the apoptotic
degeneration of spinal cord neurons, including motor neurons, over
several weeks. Motor neuron loss was markedly potentiated by the
inhibition of glutamate transport. Motor neuron toxicity could be
entirely prevented by the antioxidant N-acetylcysteine and, to a lesser
extent, by a non-NMDA glutamate receptor antagonist. The findings
suggested that loss of motor neurons in familial ALS may result from
decreased SOD1 activity and may possibly be potentiated by inefficient
glutamate transport.

In experiments that McCabe (1995) referred to as 'modeling Lou Gehrig's
disease in the fruit fly,' Phillips et al. (1995) demonstrated that
mutations in the Sod1 gene resulted in striking neuropathology in
Drosophila. Heterozygotes with 1 wildtype and 1 deleted Sod allele
retained the expected 50% of normal activity for this dimeric enzyme.
However, heterozygotes with 1 wildtype and 1 missense Sod allele showed
decreased Sod activities, ranging from 37% for a heterozygote carrying a
missense mutation predicted from structural models to destabilize the
dimer interface to an average of 13% for several heterozygotes carrying
missense mutations predicted to destabilize the subunit fold. Genetic
and biochemical evidence suggested a model of dimer disequilibrium
whereby SOD activity in missense heterozygotes is reduced through
entrapment of wildtype subunits into unstable or enzymatically inactive
heterodimers.

In mice, Bruijn et al. (1998) found that neither a 6-fold increase in
wildtype Sod1 nor its complete elimination affected the accumulated
levels of mutant Sod1(G85R) protein. Thus, despite a decreased stability
of Sod1(G85R) relative to wildtype Sod1 in the transgenic mice, the
wildtype protein did not stabilize mutant Sod1. Moreover, the presence
of Sod1(G85R) had no effect on the level or the activity of wildtype
Sod1. Both elimination and elevation of wildtype Sod1 had no effect on
mutant-mediated disease, which demonstrated that use of SOD mimetics is
unlikely to be an effective therapy. The findings raised the question of
whether toxicity arises from superoxide-mediated oxidative stress.
Bruijn et al. (1998) demonstrated that aggregates containing SOD1 were
common to disease caused by different mutants, implying that
coaggregation of an unidentified essential component or components, or
aberrant catalysis by misfolded mutants may underlie mutant-mediated
toxicity.

Neurofilament aggregates are pathologic hallmarks of both sporadic and
SOD1-mediated familial ALS. In transgenic mice with disruption of the
gene encoding the major neurofilament subunit required for filament
assembly (NEFL; 162280), Williamson et al. (1998) found that onset and
progression of the disease caused by the familial ALS-associated Sod1
mutant G85R were significantly slowed, while selectivity of
mutant-mediated toxicity for motor neurons was reduced. In Nefl-deleted
animals, levels of the 2 remaining neurofilament subunits, Nefm (162250)
and Nefh (162230), were markedly reduced in axons but elevated in motor
neuron cell bodies. Thus, while neither perikaryal nor axonal
neurofilaments were essential for Sod1-mediated disease, the absence of
assembled neurofilaments both diminished selective vulnerability and
slowed Sod1(G85R) mutant-mediated toxicity to motor neurons.

Nguyen et al. (2001) observed a correlation between Cdk5 (123831)
activity and the longevity of transgenic mice with differing expression
levels of the G37R mutant Sod1. Nguyen et al. (2001) bred the G37R
transgene onto neurofilament mutant backgrounds and observed that the
absence of NEFL provoked an accumulation of unassembled neurofilament
subunits in the perikaryon of motor neurons and extended the average
life span of the mutant mice.

In mice, Pasinelli et al. (2000) confirmed that activation of caspase-1
(CASP1; 147678) is an early event in the mechanism of toxicity from Sod1
mutants. However, neuronal death followed only after months of chronic
caspase-1 activation, concomitantly with activation of caspase-3 (CASP3;
600636), the final step in the toxic cascade. Thus, the toxicity of
mutant SOD1 is a sequential activation of at least 2 caspases, a chronic
initiator and a final effector of cell death.

Kunst et al. (2000) studied the mouse model of ALS generated by Ripps et
al. (1995) using a G86R mutation that corresponds to the human G85R
mutation. Expression of the ALS phenotype in mice carrying this mutation
was highly dependent upon the mouse genetic background, which is similar
to the phenotypic variation observed in ALS patients carrying identical
SOD1 mutations. In 1 background, mice developed an ALS phenotype at
approximately 100 days. However, when these mice were bred into a mixed
background, the onset was delayed (143 days to more than 2 years). Using
129 polymorphic autosomal markers in a genomewide scan, Kunst et al.
(2000) identified a major genetic modifier locus with a maximum lod
score of 5.07 on mouse chromosome 13. This 5- to 8-cM interval contains
the spinal muscular atrophy (SMA)-associated gene Smn (600354) and 7
copies of the Naip gene (600355), suggesting a potential link between
SMA and ALS.

Oeda et al. (2001) generated transgenic C. elegans strains containing
wildtype and mutant human A4V (147450.0012), G37R (147450.0001), and
G93A (147450.0008) SOD1 recombinant plasmids. The transgenic strains
expressing mutant human SOD1 showed greater vulnerability to oxidative
stress induced by 0.2 mM paraquat than a control that contained the
wildtype human SOD1. In the absence of oxidative stress, mutant human
SOD1 proteins were degraded more rapidly than the wildtype human SOD1
protein in C. elegans. In the presence of oxidative stress, however,
this rapid degradation was inhibited, and the transgenic C. elegans
coexpressing mutant human SOD1 demonstrated discrete aggregates in
muscle tissue. These results suggested that oxidative damage inhibits
the degradation of familial ALS-associated SOD1 mutant proteins,
resulting in an aberrant accumulation of mutant proteins that might
contribute to cytotoxicity.

By gene expression profiling in the diseased spinal cord of G93A
transgenic mice, Olsen et al. (2001) found extensive astrocytic and
microglial activation, as indicated by increased levels of GFAP (137780)
and vimentin (193060), among others. There was also an increase in APOE
(107741), perhaps reflecting myelin degeneration in peripheral nerves
and consequent lipid turnover. This was followed by activation of genes
involved in metal ion regulation, which the authors suggested represents
a protective homeostatic response to limit metal-catalyzed free radical
oxidative damage.

In murine cells, Raoul et al. (2002) showed that Fas (134637) triggers
cell death specifically in motor neurons by transcriptional upregulation
of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase
(600289). ASK1 (602448) and Daxx (603186) act upstream of p38 in the Fas
signaling pathway. The authors also showed that synergistic activation
of the NO pathway and the classic FADD (602457)/caspase-8 (601763) cell
death pathway were needed for motor neuron cell death. No evidence for
involvement of the Fas/NO pathway was found in other cell types. Motor
neurons from transgenic mice expressing ALS-linked SOD1 mutations
displayed increased susceptibility to activation of the Fas/NO pathway.
Raoul et al. (2002) emphasized that this signaling pathway was unique to
motor neurons and suggested that these cell death pathways may
contribute to motor neuron loss in ALS.

Howland et al. (2002) created a transgenic rat model of ALS. Transgenic
overexpression of the SOD1 gene harboring the G93A mutation resulted in
ALS-like motor neuron disease. Motor neuron disease in these rats
depended on high levels of mutant SOD1 expression. Disease onset was
early, and progression was rapid thereafter, with affected rats reaching
end stage on average within 11 days. Pathologic abnormalities included
vacuoles initially in the lumbar spinal cord and subsequently in more
cervical areas. Vacuolization and gliosis were evident before clinical
onset of disease and before motor neuron death in the spinal cord and
brainstem. Focal loss of the EAAT2 glutamate receptor (SLC1A2; 600300)
in the ventral horn of the spinal cord coincided with gliosis but
appeared before motor neuron/axon degeneration. At end-stage disease,
gliosis increased and EAAT2 loss in the ventral horn exceeded 90%,
suggesting a role for this protein in the events leading to cell death
in ALS.

Subramaniam et al. (2002) bred Ccs (603864) heterozygotes to Sod1
heterozygotes to generate double-knockout mice. Motor neurons in Ccs -/-
mice showed increased rate of death after facial nerve axotomy, a
response documented for Sod1 -/- mice. Thus, CCS is necessary for the
efficient incorporation of copper into SOD1 in motor neurons. Although
the absence of Ccs led to a significant reduction in the amount of
copper-loaded mutant Sod1, it did not modify the onset and progression
of motor neuron disease in Sod1-mutant mice. Subramaniam et al. (2002)
concluded that CCS-dependent copper loading of mutant SOD1 plays no role
in the pathogenesis of motor neuron disease in these mouse models.

Mattiazzi et al. (2002) examined mitochondria from transgenic mice
expressing wildtype and G93A mutated human SOD1. They found that a
significant proportion of enzymatically active SOD1 was localized in the
intermembrane space of mitochondria. Presymptomatic G93A transgenic mice
did not show significant mitochondrial abnormalities. Upon onset of
disease, however, mitochondrial respiration, electron transfer, and ATP
synthesis were disrupted. There was also oxidative damage to
mitochondrial proteins and lipids.

Kirby et al. (2002) investigated alterations in gene expression by
transfecting the murine motor neuronal cell line NSC34 with normal or
mutant Cu/Zn SOD constructs. Presence of the mutant Cu/Zn SOD led to a
decrease in expression of KIF3B (603754), a kinesin-like protein, which
forms part of the KIF3 molecular motor. c-Fes (190030), thought to be
involved in intracellular vesicle transport, was also decreased, further
implicating the involvement of vesicular trafficking as a mode of action
for mutant Cu/Zn SOD. In addition, a decrease was confirmed in ICAM1
(147840), a response in part due to the increased expression of SOD1,
and decreased Bag1 (601497) expression was confirmed in 2 of 3 mutant
cell lines, providing further support for the involvement of apoptosis
in SOD1-associated motor neuron death.

Allen et al. (2003) determined that expression of human SOD1 carrying
the G93A or G37R substitution in mouse motor neuron cultures resulted in
the differential expression and altered function of proteins that
regulate nitric oxide metabolism, intracellular redox conditions, and
protein degradation. There was also significantly reduced total GST (see
134660) activity and significantly reduced activity of several
proteasome enzymes.

Clement et al. (2003) found that in chimeric mice that are mixtures of
normal and SOD1 mutant-expressing cells, toxicity to motor neurons
required damage from mutant SOD1 acting within nonneuronal cells. Normal
motor neurons in SOD1 mutant chimeras developed aspects of ALS
pathology. Most important, nonneuronal cells that did not express mutant
SOD1 delayed degeneration and significantly extended survival of
mutant-expressing motor neurons.

Guo et al. (2003) generated transgenic mice overexpressing the glutamate
transported EAAT2 and crossed these with mice bearing the ALS-associated
SOD1 mutant G93A (147450.0008). The amount of EAAT2 protein and the
associated Na(+)-dependent glutamate uptake was increased about 2-fold
in EAAT2 transgenic mice. The transgenic EAAT2 protein was properly
localized to the cell surface on the plasma membrane. Increased EAAT2
expression protected neurons from L-glutamate-induced cytotoxicity and
cell death in vitro. The EAAT2/G93A double transgenic mice showed a
statistically significant delay in grip strength decline but not in the
onset of paralysis, body weight decline, or life span when compared with
G93A littermates. A delay in the loss of motor neurons and their axonal
morphologies, as well as other events including caspase-3 activation and
SOD1 aggregation, were also observed. The authors hypothesized that loss
of EAAT2 may contribute to, but does not cause, motor neuron
degeneration in ALS.

Wang et al. (2003) demonstrated motor neuron disease in transgenic mice
expressing a SOD1 variant that mutates the 4 histidine residues (e.g.,
H46R, 147450.00013) that coordinately bind copper. The accumulation of
detergent-insoluble forms of SOD1 included full-length SOD1 proteins,
peptide fragments, stable oligomers, and ubiquitinated entities.
Moreover, chaperones Hsp25 (HSPB1; 602195) and alpha-B-crystallin
(CRYAB; 123590) specifically cofractionated with insoluble SOD1.
Expression of recombinant peptide fragments of wildtype SOD1 in cultured
cells also produced insoluble species, suggesting that SOD1 possesses
elements with an intrinsic propensity to aggregate.

Mitochondrial dysfunction, occurring not only in motor neurons but also
in skeletal muscle, may play a critical role in the pathogenesis of ALS.
In this regard, the life expectancy of transgenic mice carrying the
human G93A mutation in the SOD1 gene is extended by creatine, an
intracellular energy shuttle that ameliorates muscle function. Moreover,
a population of patients with sporadic ALS exhibits a generalized
hypermetabolic state (Desport et al., 2001). These findings led Dupuis
et al. (2004) to explore whether alterations in energy homeostasis may
contribute to the disease process. In 2 strains of transgenic ALS mice,
those with the G86R mutation in murine Sod1 or the G93A mutation in
human SOD1, the authors showed important variations in a number of
metabolic indicators, indicating a metabolic deficit. These alterations
were accompanied early in the asymptomatic phase of the disease by
reduced adipose tissue accumulation, increased energy expenditure, and
concomitant skeletal muscle hypermetabolism. Compensating this energetic
imbalance with a highly energetic diet extended mean survival by 20%.
Dupuis et al. (2004) suggested that hypermetabolism, mainly of muscular
origin, may represent by itself an additional driving force involved in
increasing motor neuron vulnerability.

Using various immunoprecipitation and crosslinking experiments,
Pasinelli et al. (2004) demonstrated that both wildtype and mutant SOD1
(G93A) interacted directly with the antiapoptotic protein BCL2 (151430)
in both mouse and human spinal cord. The authors also found that BCL2
bound to mutant SOD1-containing aggregates in spinal cord mitochondria
from both ALS mice (G93A) and an ALS patient with the A4V mutation
(147450.0012). These aggregates were not identified in liver
mitochondria, suggesting that spinal cord neurons are particularly
susceptible to mutant SOD1. Pasinelli et al. (2004) suggested that
entrapment of BCL2 by mutant SOD1 aggregates may deplete motor neurons
of this antiapoptotic protein, resulting in decreased cell survival.

Liu et al. (2004) found that multiple disease-causing SOD1 mutants,
including G37R (147450.0001), G85R (147450.0006), G93A (147450.0008),
and H46R (147450.0013), but not wildtype SOD1, were imported selectively
into the mitochondria of mouse spinal cord neurons, but not in
unaffected tissues such as skeletal muscle and liver. The G37R SOD1
mutant was uniquely associated with brain mitochondria. The SOD1 mutants
and covalently modified adducts of them accumulated as protein
aggregates within the mitochondria. Similar findings were seen in spinal
cord tissue from a patient with ALS caused by a SOD1 mutation. The
findings were independent of the copper chaperone for SOD1 and dismutase
activity of the specific mutations. Liu et al. (2004) concluded that the
universal association of SOD1 mutants with mitochondria selectively in
affected tissues represents a common property of these mutants that
generates a cascade of damage to the motor neuron.

Wang et al. (2005) found that in L126X (147450.0026)-transgenic mice
detergent-insoluble mutant protein specifically accumulated in
somatodendritic compartments. Soluble forms of the mutant protein were
undetectable in spinal cord at any age and the levels of accumulated
protein directly correlated with disease symptoms. In vitro,
alpha-B-crystallin suppressed aggregation of mutant SOD1. In vivo,
alpha-B-crystallin immunoreactivity was most abundant in
oligodendrocytes and upregulated in astrocytes of symptomatic mice;
neither of these cell types accumulated mutant SOD1 immunoreactivity.
Wang et al. (2005) suggested that damage to motor neuron cell bodies and
dendrites within the spinal cord may be sufficient to induce motor
neuron disease, and that activities of chaperones may modulate the
cellular specificity of mutant SOD1 accumulation.

Perrin et al. (2005) analyzed gene expression in motor neurons during
disease progression in transgenic SOD1-G93A mice that developed motor
neuron loss. Only a small number of genes were differentially expressed
in motor neurons at a presymptomatic age (27 out of 34,000 transcripts).
There was an early specific upregulation of the gene coding for vimentin
(193060) that was increased even further during disease progression.
Vimentin expression was not only elevated in motor neurons, but the
protein formed inclusions in motor neuron cytoplasm. Time-course
analysis of motor neurons at a symptomatic age (90 and 120 days) showed
a modest deregulation of only a few genes associated with cell death
pathways; however, a massive upregulation of genes involved in cell
growth and/or maintenance was observed.

Ferri et al. (2006) found that 12 different mutant SOD1 proteins
associated with the mitochondria in mouse motoneuron cells to a greater
extent than did wildtype SOD1 protein. Mutant SOD1 proteins tended to
form crosslinked oligomers, and their presence caused a shift in the
mitochondrial redox state, resulting in impairment of respiratory
complex function. Further studies suggested that oxidative modification
of SOD1 cysteine residues was involved in the toxic phenotype.

In transgenic mice with mutations in the SOD1 gene, Deng et al. (2006)
found that overexpression of wildtype human SOD1 not only hastened the
onset of the ALS phenotype, but also converted an unaffected phenotype
to an ALS phenotype. Development of the ALS phenotype was associated
with conversion of the wildtype SOD1 from a soluble to an aggregated
form in the presence of mutant SOD1. The conversion was observed in
mitochondria of the spinal cord and involved formation of insoluble SOD1
dimers and multimers that were cross-linked through intermolecular
disulfide bonds via oxidation of cysteine residues in SOD1. The findings
provided further evidence of links among oxidation, protein aggregation,
mitochondrial damage, and ALS. In an accompanying paper, the same group
(Furukawa et al., 2006) found that a significant fraction of the
insoluble SOD1 aggregates in spinal cord of ALS mice contained disulfide
cross-linked SOD1 multimers. These multimers were found only in
mitochondria from the spinal cord of symptomatic mice and not in
unaffected tissues such as brain cortex or liver.

Using mice carrying a deletable mutant Sod1 gene, Boillee et al. (2006)
demonstrated that expression within motor neurons is a primary
determinant of ALS disease onset and of an early phase of disease
progression. Diminishing the mutant levels in microglia had little
effect on the early phase but sharply slowed later disease progression.
Boillee et al. (2006) concluded that onset and progression thus
represent distinct ALS disease phases defined by mutant action within
different cell types to generate non-cell autonomous killing of motor
neurons, and that their findings validate therapies, including cell
replacement, targeted to the nonneuronal cells.

In mice, Miller et al. (2006) demonstrated that human SOD1
mutant-mediated damage within muscles was not a significant contributor
to non-cell autonomous pathogenesis of ALS. In addition, enhancement of
muscle mass and strength provided no benefit in slowing disease onset or
progression.

Using a specific antibody that detects SOD1 conformations in which the
native dimer is disrupted or misfolded, Rakhit et al. (2007) established
the presence of small amounts of misfolded SOD1 within degenerating
motor neurons in the spinal cord from ALS mouse models with the human
G37R, G85R, and G93A SOD1 mutations. Misfolded SOD1 was found primarily
associated within the ventral horn and ventral roots in both
mitochondrial and cytosolic cell fractions. Misfolded SOD1 appeared
before the onset of symptoms and decreased at end-stage disease,
concomitant with motor neuron loss.

In murine neuroblastoma cells, Niwa et al. (2007) found that
nonphysiologic intermolecular disulfide bonds involving cys6 and cys111
of mutant SOD1 were important for high molecular weight aggregate
formation, ubiquitylation, and neurotoxicity. Aggregation was decreased
when these residues were replaced with serine. Dorfin (607119)
ubiquitylated mutant SOD1 by recognizing the cys6 and cys111-disulfide
cross-linked form and targeted it for proteasomal degradation.

Marden et al. (2007) evaluated the effects of NADPH oxidase-1 (NOX1;
300225) or Nox2 (CYBB; 300481) deletion on transgenic mice
overexpressing human SOD1 with the ALS-associated G93A mutation by
monitoring the onset and progression of disease using various indices.
Disruption of either Nox1 or Nox2 significantly delayed progression of
motor neuron disease in these mice. However, 50% survival rates were
enhanced significantly more by Nox2 deletion than Nox1 deletion. Female
mice lacking 1 copy of the X-chromosomal Nox1 or Nox2 genes also
exhibited significantly increased survival rates, suggesting that in the
setting of random X-inactivation, a 50% reduction in Nox1- or
Nox2-expressing cells has a substantial therapeutic benefit in ALS mice.
Marden et al. (2007) concluded that NOX1 and NOX2 contribute to the
progression of ALS.

Awano et al. (2009) found that canine degenerative myelopathy, a
spontaneously occurring adult-onset neurodegenerative disease, was
highly associated with a homozygous glu40-to-lys (E40K) mutation in the
canine Sod1 gene. The mutation was found in affected breeds including
the Pembroke Welsh corgi, boxer, Rhodesian ridgeback, Chesapeake Bay
retriever, and German shepherd. The disorder was characterized
clinically by adult onset of spasticity and proprioceptive ataxia,
followed by weakness, paraplegia, and hyporeflexia. Histopathologic
examination of the spinal cord of 46 affected dogs showed white matter
degeneration with axonal and myelin loss and cytoplasmic Sod1-positive
inclusions in surviving neurons. The disorder closely resembled human
ALS.

Tateno et al. (2009) demonstrated that, starting from the pre-onset
stage of ALS, misfolded SOD1 species associated specifically with Kap3
(KIFAP3; 601836) in the ventral white matter of SOD1G93A-transgenic
mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding
to cargoes including choline acetyltransferase (CHAT; 118490). Motor
axons in SOD1G93A-Tg mice also showed a reduction in CHAT transport from
the pre-onset stage. Using a purified hybrid mouse neuroblastoma/rat
glioma cell line NG108-15 transfected with SOD1 mutations, the authors
showed that microtubule-dependent release of acetylcholine was
significantly impaired by misfolded SOD1 species and that impairment was
normalized by KAP3 overexpression. KAP3 was incorporated into SOD1
aggregates in spinal motor neurons from human ALS patients as well.
Tateno et al. (2009) suggested that KAP3 sequestration by misfolded SOD1
species and the resultant inhibition of CHAT transport play a role in
the pathophysiology of ALS.

In familial and sporadic ALS and in rodent models of the disease,
alterations in the ubiquitin-proteasome system (UPS) may be responsible
for the accumulation of potentially harmful ubiquitinated proteins,
leading to motor neuron death. In the spinal cord of G93A-mutant SOD1
transgenic mice, Cheroni et al. (2009) found a decrease in constitutive
proteasome subunits during disease progression. An increased
immunoproteasome expression was also observed, which correlated with a
local inflammatory response. These findings support the existence of
proteasome modifications in ALS-vulnerable tissues. The authors crossed
SOD1-G93A mice with transgenic mice expressing a fluorescently-tagged
reporter substrate of the UPS. In double-transgenic UbG76V-GFP/SOD1-G93A
mice, an increase in UbG76V-GFP reporter, indicative of UPS impairment,
was detectable in a few spinal motor neurons and not in reactive
astrocytes or microglia. The levels of reporter transcript were
unaltered, suggesting that the accumulation of UbG76V-GFP was due to
deficient reporter degradation. In some motor neurons the increase of
UbG76V-GFP was accompanied by the accumulation of ubiquitin and
phosphorylated neurofilaments, both markers of ALS pathology. Cheroni et
al. (2009) suggested that UPS impairment occurs in motor neurons of
mutant SOD1-linked ALS mice and may play a role in the disease
progression.

Wang et al. (2009) studied the effect of wildtype SOD1 overexpression
(WTSOD1) in a G85R (147450.0006) transgenic mouse model. The G85R/WTSOD1
double-transgenic mice had an acceleration of disease onset and
shortened survival compared with mice carrying the G85R mutation alone.
In addition, there was an earlier appearance of pathologic and
immunohistochemical abnormalities. The spinal cord insoluble fraction
from G85R/WTSOD1 mice had evidence of G85R/WTSOD1 heterodimers and
WTSOD1 homodimers (in addition to G85R homodimers) with intermolecular
disulfide bond crosslinking. Wang et al. (2009) suggested that wildtype
SOD1 may be recruited into disease-associated aggregates by redox
processes, providing an explanation for the accelerated disease seen in
G85R/WTSOD1 double-transgenic mice following WTSOD1 overexpression, and
suggested the importance of incorrect disulfide-linked protein in mutant
SOD1 toxicity.

Karch et al. (2009) found that 3 transgenic mouse strains with Sod1
mutations developed accumulation of disulfide crosslinked,
detergent-insoluble, Sod1 aggregates in the spinal cord that occurred
primarily in the later stage of disease, concurrent with rapid
progression. Although the mutant protein lacking normal intramolecular
disulfide bonds was a major component of the insoluble SOD1 aggregates,
the presence of aberrant intermolecular disulfide bonds did not appear
to play a role in promoting Sod1 aggregation. Disulfide crosslinking was
likely a secondary event to mutant Sod1 proteins coming into close
proximity and forming high molecular weight structures. In addition, the
majority of mutant Sod1 was consistent with reduced Sod1. Karch et al.
(2009) proposed a model in which soluble forms of mutant SOD1 initiate
disease, with larger aggregates resulting from abnormalities in the
oxidation of intramolecular disulfide bonds only during the final stages
of disease.

Wong and Martin (2010) created transgenic mice expressing wildtype, G37R
(147450.0001), and G93A (147450.0008) human SOD1, only in skeletal
muscle. These mice developed age-related neurologic and pathologic
phenotypes consistent with ALS. Affected mice showed limb weakness and
paresis with motor deficits. Skeletal muscles developed severe pathology
involving oxidative damage, protein nitration, myofiber cell death, and
marked neuromuscular junction abnormalities. Spinal motor neurons
developed distal axonopathy, formed ubiquitinated inclusions, and
degenerated through an apoptotic-like pathway involving caspase-3
(600636). Mice expressing wildtype and mutant forms of SOD1 developed
motor neuron pathology. The authors concluded that SOD1 in skeletal
muscle has a causal role in ALS, and they proposed a nonautonomous
mechanism to explain the degeneration and selective vulnerability of
these motor neurons.

- Therapeutic Strategies in Animal Models of ALS

Kostic et al. (1997) found that overexpression of the protooncogene Bcl2
delayed onset of motor neuron disease and prolonged survival in
transgenic mice expressing the familial ALS-linked SOD1 mutation G93A.
However, the duration of the disease was unaltered. Overexpression of
Bcl2 also attenuated the magnitude of spinal cord motor neuron
degeneration in the familial ALS-transgenic mice. The studies suggested
a role for gene intervention, with the use of Bcl2 or antiapoptotic Bcl2
homologs as potential therapies for ALS.

Cleveland (1999) reviewed the pathways then known or suggested for
disease mechanism in SOD1-related ALS, diagrammed these pathways, and
summarized potential therapies in his Figure 3. He pointed out that the
best pharmacologic intervention to that time was the simple addition of
creatine to the drinking water of Sod1G93A mice. Long used by athletes
hoping to enhance energy reserves in muscle, creatine yielded a
dose-dependent extension in survival of this ALS-modeling mouse, peaking
at just under 4 weeks. How creatine provided this benefit
mechanistically was unclear, but its availability at local health food
stores made it 'a safe bet that it is already being taken widely.'

In transgenic mice expressing human G93A SOD1, Li et al. (2000) found
that intracerebroventricular administration of zVAD-fmk, a broad caspase
inhibitor, prolonged life span by 22%. Moreover, zVAD-fmk was found to
inhibit caspase-1 (147678) activity as well as caspase-1 and caspase-3
(600636) mRNA upregulation, providing evidence for a non-cell-autonomous
pathway regulating caspase expression. Li et al. (2000) found that
caspases play an instrumental role in neurodegeneration in transgenic
Sod1G93A mice, suggesting that caspase inhibition may have a protective
role in ALS. Li et al. (2000) also demonstrated that zVAD-fmk decreased
IL1-beta (147720), an indication that caspase-1 activity was inhibited.

Azzouz et al. (2000) injected the spinal cords of transgenic mice with a
G93A SOD1 mutation with a recombinant adeno-associated virus (rAAV)
encoding the antiapoptotic protein Bcl2. Injection resulted in sustained
Bcl2 expression in motor neurons and significantly increased the number
of surviving motor neurons at the end-stage of disease. Local Bcl2
expression in spinal motor neurons delayed the appearance of signs of
motor deficiency but was not sufficient to prolong the survival of mice
harboring this mutation.

Friedlander (2003) discussed apoptosis and caspases in neurodegenerative
diseases. They noted clinical trials of an inhibitor of apoptosis
(minocycline) for neurodegenerative disorders (Fink et al., 1999; Chen
et al., 2000). Zhang et al. (2003) reported that a combination of
minocycline and creatine in ALS mice with the Sod1G93A mutation resulted
in additive neuroprotection, delaying disease onset, slowing
progression, and delaying mortality.

Arimoclomol is a hydroxylamine derivative that acts as a coinducer of
heat shock protein (HSP) expression, which is increased in chronic
disease and offers a powerful cytoprotective mechanism. In ALS mice with
the SOD1 G93A mutation, Kieran et al. (2004) found that treatment with
arimoclomol resulted in delay in disease progression, improvement in
hindlimb muscle function, increase in motoneuron survival, and increase
in life span compared to untreated mutant mice. Arimoclomol prolonged
the activation of heat shock transcription factor-1 (HSF1; 140580),
resulting in an increase in HSP70 (140550) and HSP90 (140571) expression
in the treated mutant mice.

Azzouz et al. (2004) reported that a single injection of a VEGF
(192240)-expressing lentiviral vector into various muscles delayed onset
and slowed progression of ALS in mice engineered to overexpress the gene
encoding the mutated G93A form of SOD1 (147450.0008), even when
treatment was initiated at the onset of paralysis. VEGF treatment
increased the life expectancy of ALS mice by 30% without causing toxic
side effects, thereby achieving one of the most effective therapies
reported in the field to that time.

To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2
subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid (AMPA)-type glutamate receptors (see GLUR2, 138247) to SOD1-related
motoneuronal death, Tateno et al. (2004) generated choline
acetyltransferase (ChAT; 118490)-GluR2 transgenic mice with
significantly reduced Ca(2+) permeability of these receptors in spinal
motoneurons. Crossbreeding of the Sod1(G93A) transgenic mouse model of
ALS with ChAT-GluR2 mice led to marked delay of disease onset,
mortality, and the pathologic hallmarks such as release of cytochrome c
from mitochondria, induction of Cox2 (600262), and astrogliosis.
Subcellular fractionation analysis revealed that unusual SOD1 species
accumulated in 2 fractions (P1, composed of nuclei and certain kinds of
cytoskeletons such as neurofilaments and glial fibrillary acidic protein
(GFAP; 137780), and P2, composed of mitochondria) long before disease
onset and then extensively accumulated in the P1 fractions by disease
onset. All these processes for unusual SOD1 accumulation were
considerably delayed by GluR2 overexpression. Ca(2+) influx through
atypical motoneuronal AMPA receptors thus promoted a misfolding of
mutant SOD1 protein and eventual death of these neurons.

Using unbiased transcript profiling in the Sod1G93A mouse model of ALS,
Lincecum et al. (2010) identified a role for the costimulatory pathway,
a key regulator of immune responses. Furthermore, Lincecum et al. (2010)
observed that this pathway is upregulated in the blood of 56% of human
patients with ALS. A therapy using a monoclonal antibody to CD40L
(300386) was developed that slowed weight loss, delayed paralysis, and
extended survival in an ALS mouse model.

Meissner et al. (2010) found that G93A mutant SOD1 activated caspase-1
(CASP1; 147678) and CASP1-mediated secretion of mature IL1-beta (147720)
in a dose-dependent manner in microglia and macrophages. In cells in
which CASP1 was activated, there was rapid endocytosis of mutant SOD1
into the cytoplasm; autophagy of mutant SOD1 within the cytoplasm
dampened the proinflammatory response. Mutant SOD1 induced caspase
activation through a gain of amyloid conformation, not through its
enzymatic activity. Deficiency in caspase-1 or IL1-beta extended the
life span of mutant Sod1 mice and was associated with decreased
microgliosis and astrogliosis; however, age at disease onset was not
affected. Treatment of mutant mice with an IL1 receptor inhibitor also
extended survival and improved motor performance. The findings suggested
that IL1-beta contributes to neuroinflammation and disease progression
in ALS.

- Other Animal Models

To determine whether increased SOD1 protects the heart from ischemia and
reperfusion, Wang et al. (1998) performed studies in a newly developed
transgenic mouse model in which direct measurement of superoxide,
contractile function, bioenergetics, and cell death could be performed.
Transgenic mice with overexpression of human SOD1 were studied along
with matched nontransgenic controls. Immunoblotting and immunohistology
demonstrated that total SOD1 expression was increased 10-fold in hearts
from transgenic mice compared with nontransgenic controls, with
increased expression in both myocytes and endothelial cells. In
nontransgenic hearts following 30 minutes of global ischemia, a
reperfusion-associated burst of superoxide generation was demonstrated
by electron paramagnetic resonance spin trapping. However, in the
transgenic hearts with overexpression of SOD1, the burst of superoxide
generation was almost totally quenched, and this was accompanied by a
2-fold increase in the recovery of contractile function, a 2.2-fold
decrease in infarct size, and a greatly improved recovery of high energy
phosphates compared with that in nontransgenic controls. These results
demonstrated that superoxide is an important mediator of postischemic
injury and that increased intracellular SOD1 dramatically protects the
heart from this injury.

To test the hypothesis that chronic and unrepaired oxidative damage
occurring specifically in motor neurons is a critical causative factor
in aging, Parkes et al. (1998) generated transgenic Drosophila that
expressed human SOD1 specifically in adult motor neurons. The authors
showed that overexpression of the SOD1 gene in motor neurons extended
normal life span of the animals by up to 40% and rescued the life span
of a short-lived Sod null mutant. Elevated resistance to oxidative
stress suggested that the life span extension observed in these flies
was due to enhanced metabolism of reactive oxygen.

Green et al. (2002) excluded the Sod1 gene as a candidate for canine
spinal muscular atrophy.

Imamura et al. (2006) generated Sod1 -/- mice and observed age-related
changes of the retina similar to the key elements of human age-related
macular degeneration (ARMD; see 603075), including drusen, thickened
Bruch membrane, and choroidal neovascularization. Imamura et al. (2006)
suggested that oxidative stress may play a causative role in ARMD and
concluded that SOD1 has a critical role in protecting the retinal
pigment epithelium from age-related macular degeneration.

*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY37ARG

In affected members of a family with autosomal dominant amyotrophic
lateral sclerosis (105400), Rosen et al. (1993) identified a
heterozygous G-to-A transition in exon 2 of the SOD1 gene, resulting in
a gly37-to-arg (G37R) substitution.

By transient expression in primate cells, Borchelt et al. (1994) found
that the G37R mutant protein retained full specific activity, but
displayed a 2-fold reduction in polypeptide stability. The G37R mutant
displayed similar properties in transformed lymphocytes from an
individual heterozygous for the G37R and wildtype SOD1 genes;
heterodimeric enzymes composed of mutant and wildtype subunits were
detected, but there was no measurable diminution in the stability and
activity of the wildtype subunits. The authors concluded that mutants
such as G37R with modest losses in activity involving only the mutant
subunit can still result in motor neuron death. Alternatively, mutant
SOD1 may acquire properties that injure motor neurons by one or more
mechanisms unrelated to the metabolism of oxygen radicals.

.0002
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, LEU38VAL

In affected members of a family with autosomal dominant amyotrophic
lateral sclerosis (105400), Rosen et al. (1993) identified a
heterozygous C-to-G transversion in exon 2 of the SOD1 gene, resulting
in a leu38-to-val (L38V) substitution.

.0003
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY41SER

In affected members of a family with autosomal dominant amyotrophic
lateral sclerosis (105400), Rosen et al. (1993) identified a
heterozygous G-to-A transition in exon 2 of the SOD1 gene, resulting in
a gly41-to-ser (G41S) substitution.

.0004
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY41ASP

In affected members of a family with autosomal dominant amyotrophic
lateral sclerosis (105400), Rosen et al. (1993) identified a
heterozygous G-to-A transition in exon 2 of the SOD1 gene, resulting in
a gly41-to-asp (G41D) substitution.

In a baculovirus expression system in insect cells, Fujii et al. (1995)
found that the G41D enzyme exhibited 47% of wildtype SOD1 activity.

.0005
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, HIS43ARG

In affected members of a family with autosomal dominant amyotrophic
lateral sclerosis (105400), Rosen et al. (1993) identified a
heterozygous A-to-G transition in exon 2 of the SOD1 gene, resulting in
a his43-to-arg (H43R) substitution.

In a baculovirus expression system in insect cells, Fujii et al. (1995)
found that the H43R enzyme exhibited 66% of wildtype SOD1 activity.

.0006
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY85ARG

In affected members of a family with amyotrophic lateral sclerosis
(105400), Rosen et al. (1993) identified a G-to-C transversion in exon 4
of the SOD1 gene, resulting in a gly85-to-arg (G85R) substitution.

By transient expression in COS cells, Borchelt et al. (1994) found that
the G85R mutant protein was enzymatically inactive. However, Fujii et
al. (1995) found that the G85R enzyme exhibited 99% of wildtype SOD
activity in a baculovirus expression system in insect cells.

Bruijn et al. (1997) found that the G85R mutant protein retained SOD1
activity in studies of transgenic mice with the G85R mutation. However,
even low levels of the mutant protein caused motor neuron disease
characterized by extremely rapid clinical progression. Initial
indicators of disease were astrocytic inclusions that stained intensely
with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in
motor neurons. Astrocytic inclusions escalated markedly as disease
progressed, concomitant with a decrease in the glial glutamate
transporter (GLT1; 600300). The authors concluded that G85R mediates
direct damage to astrocytes, which may promote the nearly synchronous
degeneration of motor neurons.

Using the G85R mutation in transgenic mouse experiments, Bruijn et al.
(1998) demonstrated that neither elimination nor elevation of wildtype
SOD1 had any effect on mutant-mediated disease. The fact that aggregates
containing SOD1 were common to disease caused by different mutants
implied that coaggregation of an unidentified essential component or
aberrant catalysis by misfolded mutants underlies, in part,
mutant-mediated toxicity.

.0007
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY93CYS

In affected members of a family with amyotrophic lateral sclerosis
(105400), Rosen et al. (1993) identified a G-to-T transversion in exon 4
of the SOD1 gene, resulting in a gly93-to-cys (G93C) substitution.

Regal et al. (2006) reported the clinical features of 20 ALS patients
from 4 families with the G93C mutation. Mean age at onset was 45.9
years, and all patients had slowly progressive weakness and atrophy
starting in the distal lower limbs. Although symptoms gradually spread
proximally and to the upper extremities, bulbar function was preserved.
None of the patients developed upper motor neuron signs. Postmortem
findings of 1 patient showed severe loss of anterior horn cells and loss
of myelinated fibers in the posterior column and spinocerebellar tracts,
but only mild changes in the lateral corticospinal tracts. Lipofuscin
and hyaline inclusions were observed in many neurons. Patients with the
G93C mutation had significantly longer survival compared to patients
with other SOD1 mutations.

.0008
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY93ALA

In affected members of a family with amyotrophic lateral sclerosis
(105400), Rosen et al. (1993) identified a G-to-C transversion in exon 4
of the SOD1 gene, resulting in a gly93-to-ala (G93A) substitution.

Yim et al. (1996) observed that overexpression of mutant human H93A SOD1
in Sf9 insect cells resulted in enhanced generation of free radicals
compared to wildtype SOD1, as measured by the spin trapping method. The
effect was more intense at lower peroxide concentrations due to a small,
but reproducible, decrease in the value of K(m) for peroxide for the
G93A mutant, while the k(cat) was identical for the mutant and wildtype.
The G93A mutant and wildtype enzymes had identical dismutation activity.
Yim et al. (1996) concluded that ALS symptoms observed in G93A
transgenic mice were not caused by the reduction of SOD1 activity, but
rather were induced by a gain-of-function enhancement of the free
radical-generating function. The findings were consistent with x-ray
crystallographic studies showing that the active channel of the G93A
mutant is slightly larger than that of the wildtype enzyme, rendering it
more accessible to peroxide. See also Kostic et al. (1997).

Wiedau-Pazos et al. (1996) showed that the G93A mutant SOD1 enzyme
catalyzed the oxidation of a model substrate (spin trap
5,5-prime-dimethyl-1-pyrroline N-oxide) by hydrogen peroxide at a higher
rate than that seen with the wildtype enzyme. Catalysis of this reaction
by the mutant enzyme was more sensitive to inhibition by the copper
chelators diethyldithiocarbamate and penicillamine than was catalysis by
wildtype SOD1. The same 2 chelators reversed the apoptosis-inducing
effect of the mutant enzyme expressed in a neural cell line. The
findings were interpreted to mean that oxidative reactions catalyzed by
mutant SOD1 enzymes initiate the neuropathologic changes in familial
ALS.

.0009
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLU100GLY

In affected members of a family with amyotrophic lateral sclerosis
(105400), Rosen et al. (1993) identified an A-to-G transition in exon 4
of the SOD1 gene, resulting in a glu100-to-gly (E100G) substitution.

Winterbourn et al. (1995) demonstrated decreased thermal stability of
the mutant E100G enzyme. Extracts containing the mutant had an average
68% of normal SOD activity. On heating at 65 degrees centigrade, these
extracts lost activity at twice the rate of extracts containing only
normal enzyme.

.0010
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, LEU106VAL

In affected members of a family with amyotrophic lateral sclerosis
(105400), Rosen et al. (1993) identified a C-to-G transversion in exon 4
of the SOD1 gene, resulting in a leu106-to-val (L106V) substitution.

Kawamata et al. (1994) identified this mutation in a Japanese ALS
family.

.0011
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, ILE113THR

In affected members of a family with amyotrophic lateral sclerosis
(105400), Rosen et al. (1993) identified a T-to-C transition in exon 4
of the SOD1 gene, resulting in an ile113-to-thr (I113T) substitution.

Jones et al. (1993) identified the I113T substitution in 3 of 56
patients with sporadic ALS drawn from a population-based study in
Scotland. Jones et al. (1995) found the I113T mutation in 3 sporadic ALS
cases and 3 unrelated familial cases of ALS in Scotland. Because of
early death of parents of probands, together with illegitimacy in
families, some of the apparently sporadic cases may have been familial.
The average age at onset in patients with the I113T mutation was cited
as 61.2 years, with mean survival of 1.6 years.

Hayward et al. (1996) reported 6 additional cases in Scotland with the
I113T mutation and a common haplotype despite no evidence of
relatedness. Brock (1998) reported that he and his coworkers had found
another 3 cases in the north of England with the I113T mutation and the
identical genetic background, one that is rare in the general
population.

Kikugawa et al. (1997) performed mutation analyses of the SOD1 gene in
23 ALS patients (3 familial and 20 sporadic) from the Kii Peninsula of
Japan and its vicinity, where a relatively high incidence of familial
ALS had been observed. In 2 of the 23 patients, they identified
heterozygosity for the I113T mutation. The mutation had been reported to
be associated with the formation of neurofibrillary tangles, which was a
characteristic feature of ALS in the Kii Peninsula.

.0012
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, ALA4VAL

Deng et al. (1993) found that the ala4-to-val (A4V) mutation in exon 1
of the SOD1 gene is the most frequent basis for familial amyotrophic
lateral sclerosis (105400). This mutation was found in affected members
of 8 unrelated families. One of the families with the A4V mutation was
the Farr family reported by Brown (1951, 1960).

Rosen et al. (1994) confirmed that the A4V mutation is the most commonly
detected of all SOD1 mutations in familial ALS, and that it is among the
most clinically severe. In comparison with other ALS families, the exon
1 mutation is associated with reduced survival time after onset: 1.2
years as compared to 2.5 years for all other familial ALS patients.

Wiedau-Pazos et al. (1996) showed that the A4V mutant SOD1 enzyme
catalyzed the oxidation of a model substrate (spin trap
5,5-prime-dimethyl-1-pyrroline N-oxide) by hydrogen peroxide at a higher
rate than that seen with the wildtype enzyme. Catalysis of this reaction
by the mutant enzyme was more sensitive to inhibition by the copper
chelators diethyldithiocarbamate and penicillamine than was catalysis by
wildtype SOD1. The same 2 chelators reversed the apoptosis-inducing
effect of the mutant enzyme expressed in a neural cell line. The
findings were interpreted to mean that oxidative reactions catalyzed by
mutant SOD1 enzymes initiate the neuropathologic changes in familial
ALS.

Rakhit et al. (2007) used a specific SOD1 antibody to identify misfolded
SOD1 within degenerating motor neurons in the spinal cord from an
individual with ALS due to the A4V mutation. The findings provided
evidence that misfolded SOD1 plays a toxic or pathogenic role in ALS.

Saeed et al. (2009) identified a single 5.86-cM haplotype encompassing
the A4V variant in 54 white North American ALS patients that was not
found in 96 controls (p = 3 x 10(-11)), indicating a founder effect. To
determine the origin, several additional cohorts were genotyped,
including 54 North American, 3 Swedish, and 6 Italian patients with the
A4V mutation, 66 ALS patients with non-A4V SOD1 mutations, 96 patients
with sporadic ALS, and 96 white, 17 African American, 53 Chinese, 11
Amerindian, and 12 Hispanic healthy controls. The strength of
association of the white founder haplotype progressively decreased when
other ethnicities were used as controls, and almost disappeared when
compared to Amerindians, indicating that the A4V mutation was introduced
from Amerindians who migrated from Asia into North America. The
associated European haplotype was different from the North American
haplotype, indicating an Amerindian founder effect (accounting for 82%)
and a European founder effect (accounting for 18%) for A4V in North
America. Amerindians were both homozygous and heterozygous, whereas
Europeans were only homozygous, for nearby SNPs. The age of the A4V
mutation was estimated to be 458 +/- 59 years (range, 398 to 569 years).
Saeed et al. (2009) postulated that A4V was introduced into the white
population by Amerindians about 400 to 500 years ago at the time of the
Jamestown and Plymouth landings. Furthermore, there were no Amerindians
with ALS in their database, suggesting either that the mutation became
extinct in Amerindians or that they have an additional protective
effect.

.0013
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, HIS46ARG

In 2 Japanese families with unusually slow progression of ALS (105400),
Aoki et al. (1993) found an A-to-G transition in exon 2 of the SOD1 gene
that resulted in a his46-to-arg (H46R) substitution. His46 is a highly
conserved residue within the active site of the enzyme, and the mutation
was predicted to affect copper binding. The mutation was not found in 27
Japanese patients with sporadic ALS or 57 unrelated normal control
subjects. Functional expression studies showed that the mutant enzyme
activity was reduced by about 20%. Aoki et al. (1993) suggested that the
H46R substitution influences only the active site and does not interfere
with dimer formation, which had been reported for other SOD1 mutations.
Affected individuals showed a relatively mild form of the disorder, with
symptoms appearing in the arms more than 5 years after onset and bulbar
signs appearing more than 8 years after initial symptoms in the legs.
The mean survival after onset was 17.3 years in the Japanese cases as
compared with 1.5 years and 2.4 years in Caucasian families and 2.5
years in Japanese families with different mutations. Aoki et al. (1994)
presented in greater detail the data reported by Aoki et al. (1993).

Liu et al. (2000) determined that mutant H46R SOD1 binds neither Cu(2+)
nor Co(2+) at the native copper-binding site, but forms a new
copper-binding site at cys111 on the surface near the site of dimer
formation. Insertion of copper ions into SOD1 under normal conditions in
vivo requires the presence of a copper chaperone, CCS (603864). Liu et
al. (2000) hypothesized that cys111 is an intermediate docking site for
Cu(2+) during SOD1 biosynthesis and that it transfers Cu(2+) to the
final destination in the active site of the wildtype enzyme.

.0014
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, ALA4THR

Kawamata et al. (1994) made reference to a Japanese family with ALS
(105400) associated with a G-to-A transition in the SOD1 gene, resulting
in an ala4-to-thr (A4T) substitution. Nakano et al. (1994) reported this
family in full. See A4V (147450.0012) for a mutation involving the same
codon.

.0015
AMYOTROPHIC LATERAL SCLEROSIS 1
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL RECESSIVE, INCLUDED
SOD1, ASP90ALA

In 14 affected individuals from 4 unrelated Swedish or Finnish families
with ALS (105400), Andersen et al. (1995) identified a homozygous
mutation in exon 4 of the SOD1 gene, resulting in an asp90-to-ala (D90A)
substitution. Erythrocyte SOD1 activity was essentially normal. The
findings suggested that this mutation caused ALS by a gain of function
rather than by loss, and that the D90A mutation was less detrimental
than previously reported mutations. Consanguinity was present in several
of the families. The age at onset of symptoms ranged from 37 to 94 years
in 1 family in which all patients showed very similar disease
phenotypes; symptoms began with cramps in the legs, which progressed to
muscular atrophy and weakness. Upper motor neuron signs appeared after
1-4 years disease duration in all patients; none of the patients showed
signs of intellectual impairment. In a second family, onset in 2 sibs
was at the age of 40, with a phenotype similar to that of the first
family. In a third family, 3 sibs had onset at ages 20, 36, and 22
years, respectively. Four patients with apparently sporadic ALS were
also found to carry the mutations. Andersen et al. (1995) concluded that
familial ALS due to mutation in the SOD1 gene exists in both autosomal
dominant and autosomal recessive forms.

Robberecht et al. (1996) identified a heterozygous D90A mutation in
affected members of 2 families with ALS and in a patient with apparently
sporadic ALS. Aguirre et al. (1999) found the D90A mutation in
heterozygous state in affected members of 2 families and in 1 apparently
sporadic case of ALS. Direct sequencing of exons 1 through 5 showed no
additional mutations in the SOD1 gene in these patients and the D90A
mutation was not found on 150 normal chromosomes.

In a worldwide haplotype study of 28 pedigrees with the D90A mutation,
Al-Chalabi et al. (1998) found that 20 recessive families shared the
same founder haplotype, regardless of geographic location, whereas
several founders existed for the 8 dominant families. The findings
confirmed that D90A can act in a dominant fashion in keeping with all
other SOD1 mutations. Al-Chalabi et al. (1998) proposed that a tightly
linked protective factor modifies the toxic effect of mutant SOD1 in
recessive families.

Gellera et al. (2001) found homozygosity for the D90A mutation in a
sporadic case of ALS.

In 2 sibs with ALS from a family described by Khoris et al. (2000), Hand
et al. (2001) identified compound heterozygosity for D90A and D96N
(147450.0032). A third sib with the disease died before testing. Further
examination of the family identified the D90A mutation alone in 2
unaffected members and the D96N mutation alone in 4 unaffected members.
There were no individuals homozygous for either mutation, and no
unaffected individual with both mutations was identified. Hand et al.
(2001) concluded that both mutations, which occur in the same region of
the protein, are required for disease. The authors emphasized that this
is the first report of compound heterozygosity for the SOD1 gene in an
ALS patient and suggested that the findings may have implications for
the interpretation of inheritance patterns in ALS families.

Using PET scanning, Turner et al. (2007) found that ALS patients
homozygous for the D90A substitution had a 12% decrease in 5-HT1A
receptor (5HTRA1; 109760) binding potential compared to healthy
controls. The decreased binding among patients was most significant in
the temporal lobes. Patients with sporadic ALS without the D90A
substitution had a 21% decrease in binding potential. Turner et al.
(2007) suggested that patients with the D90A mutation may have decreased
cortical vulnerability compared to other ALS patients, which may
correlate with the slower progression observed in D90A carriers.

.0016
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL RECESSIVE
SOD1, ILE104PHE

In a Japanese family transmitting amyotrophic lateral sclerosis (105400)
with marked phenotypic variability, Ikeda et al. (1995) identified an
A-to-T mutation in exon 4 of the SOD1 gene, resulting in an
ile104-to-phe (I104F) substitution within a highly conserved loop VI
Greek key domain. This same domain has been affected by other
disease-associated SOD1 mutations (L106V; 147450.0010 and I113T;
147450.0011). The activity of the mutant I104F enzyme was decreased by
43%. Age of onset varied from 6 to 55 years with initial symptoms either
in the lower or upper extremities. The duration of the disease varied
from 3 to 38 years. Two asymptomatic carriers who died from other causes
at ages 59 and 34, respectively, had affected offspring.

.0017
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, LEU144SER

Sapp et al. (1995) reported a leu144-to-ser (L144S) mutation in the SOD1
gene in a family with apparently slow progression of amyotrophic lateral
sclerosis (105400). This substitution is in close proximity to the
active center of the SOD1 enzyme at arginine 143.

.0018
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, ALA145THR

Sapp et al. (1995) reported an ala145-to-thr (A145T) mutation in the
SOD1 gene in a family with amyotrophic lateral sclerosis (105400).

.0019
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, IVS4AS, T-G, -10

In affected members of a family with ALS (105400), Sapp et al. (1995)
identified a T-to-G transversion in intron 4 of the SOD1 gene, resulting
in an alternatively spliced mRNA and a SOD1 protein with 3 amino acids
(phe-leu-gln) inserted between exons 4 and 5 following residue 118.

.0020
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, CYS6PHE

Morita et al. (1996) identified a 2-bp mutation in exon 1 of the SOD1
gene in a 59-year-old woman who developed rapidly progressive ALS
(105400). The mutation predicted a cys6-to-phe (C6F) substitution.
Erythrocyte SOD1 activity was 25.3% of control values. Since the only
other affected family member was the deceased father, segregation of the
mutation with the disorder was not confirmed.

.0021
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, ILE151THR

In a woman with ALS (105400), Kostrzewa et al. (1996) identified a
T-to-C transition in exon 5 of the SOD1 gene, resulting in an
ile151-to-thr (I151T) substitution. The patient had onset at age 48
years of progressive dysarthria and dysphagia, followed 9 months later
by distal weakness of the legs and then weakness of her left hand. The
mutation appeared to affect formation of dimers of the protein and was
the most C-terminal amino acid change in SOD1 described to that time.
(Kostrzewa et al. (1996) mistakenly stated that the T-to-C transition
resulted in the 'substitution of an isoleucine (ATC) for a threonine
(ACC)' but also stated that 'the isoleucine at position 151...is
evolutionarily highly conserved in most vertebrates.')

.0022
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLU21LYS

In a Scottish patient with sporadic ALS (105400), Jones et al. (1994)
identified a G-to-A transition in the SOD1 gene, resulting in a
glu21-to-lys (E21K) substitution. The transition occurs at a CpG
dinucleotide and may have arisen via deamination of methylcytosine.

.0023
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, SER134ASN

In a 65-year-old Japanese man with ALS (105400), Watanabe et al. (1997)
identified a mutation in the SOD1 gene, resulting in a ser134-to-asn
(S134N) substitution. The patient had first noted right lower limb
muscle weakness at age 63. The proband's younger brother was also
affected with onset of muscle weakness at age 52, followed by rapidly
progressive muscle weakness and atrophy of all limbs, and bulbar signs.
He died of respiratory disease 9 months after onset. Although neither
patient showed upper motor neuron signs throughout the course of the
disease, the finding of an SOD1 mutation was consistent with a form of
familial ALS. Both parents died of disorders other than neurologic
diseases at ages 84 and 49, respectively. Other relatives of the patient
had no similar neurologic disease.

.0024
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, LEU84VAL

In a Japanese family with 4 members affected by ALS (105400) in 3
generations, Aoki et al. (1995) identified a mutation in the SOD1 gene
that resulted in a leu84-to-val (L84V) substitution. The enzymatic
activity of Cu/Zn SOD of skin fibroblasts was reduced to 75% of control
values. The progression of the disease was very rapid, but the age of
onset varied with sex and with generation within the family. The proband
first noted weakness and atrophy in the left hand at age 38 years.
Within 3 months, weakness developed in all 4 extremities and he died of
pneumonia 1.5 years after the onset of the disease.

.0025
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY16SER

In a patient with ALS (105400), Kawamata et al. (1997) identified a
G-to-A transition in the SOD1 gene, resulting in a gly16-to-ser (G16S)
substitution. The patient noted difficulty in writing at age 18 years.
Thereafter, muscle weakness progressed rapidly and the patient could not
walk unassisted. Mechanical ventilation was required at age 19.

.0026
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, LEU126TER

In a 58-year-old male with a family history of ALS (105400) and with a
personal history of progressive muscle weakness and atrophy for 4 years,
Zu et al. (1997) found a T-to-A transversion in the SOD1 gene, resulting
in a leu126-to-ter (L126X) substitution. The mutation resulted in the
truncation of most of the polypeptide segment encoded by exon 5 and
resulted in a familial ALS phenotype similar to that observed in
patients with missense mutations in the SOD1 gene, establishing that
exon 5 is not required for the toxic functions of mutant SOD1 associated
with ALS. The mutant enzyme was present at very low levels in the
patient, suggesting elevated toxicity compared to mutant enzymes with
single site substitutions. This increased toxicity probably arose from
the extreme structural and functional changes in the active site
channel, beta-barrel fold, and dimer interface observed in the mutant
enzyme, including the loss of native dismutase activity. In particular,
the truncation of the polypeptide chain dramatically opens the active
site channel, resulting in a marked increase in the accessibility and
flexibility of the metal ions and side chain ligands of the active site
of the enzyme. Zu et al. (1997) proposed that these structural changes
cause a decrease in substrate specificity and an increase in the
catalysis of harmful chemical reactions such as peroxidation.

.0027
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, IVS4AS, A-G, -11

In a 72-year-old male with a family history of ALS (105400) and slowly
progressive symptoms of muscle weakness and atrophy, Zu et al. (1997)
identified an intronic mutation (A-to-G) in SOD1 at the nucleotide 11
bases upstream from the intron-junction of exon 5. This splice junction
mutation resulted in alternative splicing in the mRNA with truncation of
most of the polypeptide segment encoded by exon 5. The consequences were
thought to be similar to those of the leu126-to-ter mutation
(147450.0026).

.0028
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY72SER

Orrel et al. (1997) found a heterozygous gly72-to-ser (G72S)
substitution in exon 3 of the SOD1 gene in a brother and sister with ALS
(105400). The brother had onset at age 47 with weakness of the right
foot; the sister had died with a diagnosis of ALS at the age of 49
years. This was the first exon 3 mutation to be described; over 50
different mutations involving exons 1, 2, 4, and 5 had previously been
described.

.0029
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY12ARG

In a 67-year-old patient with familial ALS (105400), Penco et al. (1999)
identified a mutation in exon 1 of the SOD1 gene, resulting in a
gly12-to-arg (G12R) substitution in a region outside the active site of
the enzyme. The substitution may lead to local distortion strain in the
protein structure. The enzymatic activity of the mutated SOD1 was 80% of
normal. The patient had onset of symptoms at age 63 years, and the
disorder showed unusually slow progression. The patient's father had
died at age 59 with a diagnosis of ALS recognized during the last year
of his life. His clinical features were very similar to those observed
in the proband. His first symptoms were walking difficulties associated
with weak leg muscles. Tendon reflexes were markedly hyperactive, but
Achilles reflexes were absent. Hand and bulbar involvement started late
in the course of the illness.

Penco et al. (1999) had originally identified this mutation as GLY12ALA.
Gellera et al. (2001) pointed out that the mutation was in fact a change
from GGC (gly) to CGC (arg). They likewise described a patient with
slowly progressive ALS due to a G12R substitution in exon 1 of the SOD1
gene.

.0030
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, PHE45CYS

In a familial case of slowly progressing ALS (105400), Gellera et al.
(2001) found a de novo T-to-G transversion in exon 2 of the SOD1 gene,
resulting in a phe45-to-cys (F45C) substitution. Onset occurred at 59
years of age in the distal muscles of the upper limbs.

.0031
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, HIS80ARG

In a 24-year-old man with sporadic ALS (105400), Alexander et al. (2002)
identified a heterozygous 112A-G transition in exon 4 of the SOD1 gene,
resulting in a his80-to-arg (H80R) substitution. The patient presented
with a 4-month history of left leg weakness, and developed rapidly
progressive weakness in all 4 limbs and bulbar musculature, manifesting
as quadriplegia, dysarthria, and dysphagia over the subsequent 8 months.
He died from pneumonia 18 months after the onset of symptoms.
Neuropathologic examination showed anterior horn cell degeneration,
prominent gliosis, and Bunina bodies in both the spinal cord and brain
stem. There was no involvement of the corticospinal tract. Ubiquitinated
inclusions were demonstrated within anterior horn cells, and
SOD1-immunoreactive inclusions were identified. There was no family
history of any form of neuromuscular disorder. His parents, maternal
grandfather, and 2 sibs did not carry the mutation, and it was not
identified in 150 unaffected Irish controls. (Alexander et al. (2002)
reported the mutation as histidine to arginine at codon 80, but
incorrectly symbolized the mutation as H80A.)

.0032
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL RECESSIVE
SOD1, ASP96ASN

In 2 sibs with ALS (105400) from a family described by Khoris et al.
(2000), Hand et al. (2001) identified compound heterozygosity for 2
mutations in the SOD1 gene: a G-to-A transition resulting in an
asp96-to-asn substitution (D96N), and D90A (147450.0015). A third sib
with the disease died before testing. Further examination of the family
identified the D90A mutation alone in 2 unaffected members and the D96N
mutation alone in 4 unaffected members. There were no individuals
homozygous for either mutation, and no unaffected individual with both
mutations was identified. Hand et al. (2001) concluded that both
mutations, which occur in the same region of the protein, are required
for disease. The authors emphasized that this was the first report of
compound heterozygosity for the SOD1 gene in an ALS patient and
suggested that the findings may have implications for the interpretation
of inheritance patterns in ALS families.

.0033
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, GLY93ARG

In affected members of a family segregating amyotrophic lateral
sclerosis (105400), Elshafey et al. (1994) identified a gly93-to-arg
(G93R) mutation in exon 4 of the SOD1 gene.

.0034
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, 6-BP DEL, GGACCA

In a Canadian patient of Filipino origin with ALS (105400), Zinman et
al. (2009) identified a homozygous 6-bp deletion (GGACCA) in exon 2 of
the SOD1 gene, resulting in the removal of 2 amino acids (gly27 and
pro28) in a conserved part of loop II. The patient had onset of leg and
arm weakness at age 51, and later developed bulbar symptoms with death
from respiratory failure at age 55. The diagnosis was confirmed by
autopsy. The patient's father and paternal uncle were also affected and
died at ages 66 and 58, respectively. Genotyping of available family
members identified 8 unaffected heterozygous carriers and a common
haplotype, consistent with a founder effect. Reconstruction of the
genotype in the patient's affected father showed that he was
heterozygous for the mutation. SOD1 undergoes naturally occurring
alternative splicing of exon 2, and the mutation was predicted to
enhance this splicing. RT-PCR studies showed alternative splicing with 2
transcripts: 1 without exon 2 and another without exons 2 and 3, both of
which result in premature termination. The abundance of the transcript
lacking exons 2 and 3 was similar in all individuals, including an
individual without the mutation. However, expression of the transcript
without exon 2 was enhanced in mutation carriers, with the highest
abundance in the homozygous proband. Spinal cord samples from the
proband showed significantly decreased SOD1 protein expression (40% less
than wildtype), and erythrocytes showed 50% decreased SOD1 enzyme
activity. The mutation was not found in 179 Filipino controls. Zinman et
al. (2009) concluded that the 6-bp deletion represents a reduced
penetrance allele in the heterozygous state, resulting from modification
of naturally occurring alternative splicing.

.0035
AMYOTROPHIC LATERAL SCLEROSIS 1
SOD1, IVS4AS, C-G, -304

In affected members of a French family with ALS1 (105400), Valdmanis et
al. (2009) identified a heterozygous C-to-G transversion in intron 4 of
the SOD1 gene (358-304C-G), resulting in the inclusion of a 43-bp
cryptic exon 304 bp before exon 5 in the SOD1 mRNA. This resulted in the
introduction of 7 amino acids before a stop codon, causing premature
termination of the protein product. Valdmanis et al. (2009) noted the
unusual genetic mechanism involved and emphasized the difficulty in
detecting such a mutation.

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165. Wang, P.; Chen, H.; Qin, H.; Sankarapandi, S.; Becher, M. W.;
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166. Watanabe, M.; Aoki, M.; Abe, K.; Shoji, M.; Iizuka, T.; Ikeda,
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*FIELD* CN
George E. Tiller - updated: 8/27/2013
George E. Tiller - updated: 8/20/2013
Cassandra L. Kniffin - updated: 2/27/2013
Marla J. F. O'Neill - updated: 5/11/2012
George E. Tiller - updated: 10/28/2010
Cassandra L. Kniffin - updated: 9/27/2010
George E. Tiller - updated: 7/7/2010
Ada Hamosh - updated: 6/18/2010
Cassandra L. Kniffin - updated: 3/29/2010
Cassandra L. Kniffin - updated: 12/17/2009
George E. Tiller - updated: 11/25/2009
George E. Tiller - updated: 10/23/2009
George E. Tiller - updated: 8/12/2009
George E. Tiller - updated: 7/22/2009
Cassandra L. Kniffin - updated: 6/22/2009
George E. Tiller - updated: 1/9/2009
Patricia A. Hartz - updated: 8/13/2008
Patricia A. Hartz - updated: 7/22/2008
Patricia A. Hartz - updated: 7/15/2008
Cassandra L. Kniffin - updated: 3/26/2008
Cassandra L. Kniffin - updated: 2/29/2008
Cassandra L. Kniffin - updated: 12/21/2007
Cassandra L. Kniffin - reorganized: 11/14/2007
Cassandra L. Kniffin - updated: 11/13/2007
Cassandra L. Kniffin - updated: 6/22/2007
George E. Tiller - updated: 4/5/2007
Cassandra L. Kniffin - updated: 3/30/2007
Paul J. Converse - updated: 1/17/2007
Marla J. F. O'Neill - updated: 9/29/2006
Patricia A. Hartz - updated: 9/7/2006
Ada Hamosh - updated: 7/24/2006
Cassandra L. Kniffin - updated: 6/14/2006
Cassandra L. Kniffin - updated: 5/24/2006
Cassandra L. Kniffin - updated: 4/20/2006
George E. Tiller - updated: 1/31/2006
George E. Tiller - updated: 10/20/2005
Cassandra L. Kniffin - updated: 6/9/2005
Cassandra L. Kniffin - updated: 5/11/2005
Cassandra L. Kniffin - updated: 4/14/2005
Victor A. McKusick - updated: 9/30/2004
Victor A. McKusick - updated: 5/12/2004
Ada Hamosh - updated: 10/29/2003
Victor A. McKusick - updated: 7/14/2003
George E. Tiller - updated: 7/14/2003
Cassandra L. Kniffin - updated: 6/9/2003
Victor A. McKusick - updated: 5/30/2003
Cassandra L. Kniffin - updated: 4/28/2003
Patricia A. Hartz - updated: 3/14/2003
Victor A. McKusick - updated: 2/3/2003
Cassandra L. Kniffin - updated: 1/30/2003
Cassandra L. Kniffin - updated: 1/9/2003
Victor A. McKusick - updated: 12/27/2002
Dawn Watkins-Chow - updated: 11/5/2002
Victor A. McKusick - updated: 10/1/2002
Victor A. McKusick - updated: 8/28/2002
Victor A. McKusick - updated: 5/17/2002
Ada Hamosh - updated: 3/28/2002
Victor A. McKusick - updated: 3/5/2002
George E. Tiller - updated: 2/13/2002
Paul J. Converse - updated: 2/13/2002
Victor A. McKusick - updated: 1/4/2002
Victor A. McKusick - updated: 11/9/2001
Victor A. McKusick - updated: 1/16/2001
Ada Hamosh - updated: 9/19/2000
George E. Tiller - updated: 4/25/2000
Ada Hamosh - updated: 4/13/2000
Victor A. McKusick - updated: 2/24/2000
Ada Hamosh - updated: 12/22/1999
Victor A. McKusick - updated: 9/8/1999
Victor A. McKusick - updated: 3/2/1999
Victor A. McKusick - updated: 1/6/1999
Victor A. McKusick - updated: 11/5/1998
Victor A. McKusick - updated: 9/15/1998
Victor A. McKusick - updated: 5/27/1998
Victor A. McKusick - updated: 5/21/1998
Victor A. McKusick - updated: 5/16/1998
Victor A. McKusick - updated: 5/5/1998
Victor A. McKusick - updated: 9/10/1997
Victor A. McKusick - updated: 9/4/1997
Victor A. McKusick - updated: 8/12/1997
Victor A. McKusick - updated: 6/23/1997
Victor A. McKusick - updated: 6/9/1997
Victor A. McKusick - updated: 2/28/1997
Stylianos E. Antonarakis - updated: 7/3/1996
Orest Hurko - updated: 5/14/1996
Moyra Smith - edited: 4/25/1996
Orest Hurko - updated: 4/1/1996
Orest Hurko - updated: 3/9/1996
Orest Hurko - updated: 8/11/1995

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 11/12/2013
carol: 9/3/2013
tpirozzi: 8/28/2013
alopez: 8/28/2013
tpirozzi: 8/27/2013
tpirozzi: 8/21/2013
tpirozzi: 8/20/2013
carol: 7/24/2013
carol: 5/29/2013
carol: 3/7/2013
ckniffin: 2/27/2013
carol: 9/19/2012
terry: 6/6/2012
carol: 5/30/2012
carol: 5/11/2012
wwang: 11/9/2010
terry: 10/28/2010
wwang: 9/29/2010
ckniffin: 9/27/2010
wwang: 7/19/2010
terry: 7/7/2010
alopez: 6/21/2010
terry: 6/18/2010
wwang: 4/6/2010
ckniffin: 3/29/2010
wwang: 1/15/2010
ckniffin: 12/17/2009
terry: 12/16/2009
wwang: 12/4/2009
terry: 11/25/2009
wwang: 11/3/2009
terry: 10/23/2009
wwang: 8/25/2009
terry: 8/12/2009
wwang: 8/7/2009
terry: 7/22/2009
wwang: 7/21/2009
ckniffin: 6/22/2009
terry: 4/8/2009
terry: 2/3/2009
wwang: 1/9/2009
mgross: 8/13/2008
mgross: 7/22/2008
mgross: 7/15/2008
wwang: 6/5/2008
wwang: 5/29/2008
ckniffin: 3/26/2008
wwang: 3/19/2008
ckniffin: 2/29/2008
wwang: 1/4/2008
ckniffin: 12/21/2007
carol: 11/14/2007
ckniffin: 11/13/2007
wwang: 7/5/2007
ckniffin: 6/22/2007
alopez: 4/11/2007
terry: 4/5/2007
wwang: 3/30/2007
wwang: 2/22/2007
ckniffin: 2/19/2007
mgross: 1/17/2007
wwang: 10/23/2006
ckniffin: 10/3/2006
wwang: 9/29/2006
mgross: 9/7/2006
alopez: 7/28/2006
terry: 7/24/2006
ckniffin: 6/26/2006
carol: 6/20/2006
ckniffin: 6/14/2006
wwang: 6/5/2006
ckniffin: 5/24/2006
wwang: 4/25/2006
ckniffin: 4/20/2006
wwang: 2/6/2006
terry: 1/31/2006
joanna: 12/6/2005
alopez: 10/20/2005
terry: 10/12/2005
wwang: 6/15/2005
ckniffin: 6/9/2005
wwang: 5/18/2005
wwang: 5/16/2005
ckniffin: 5/11/2005
wwang: 5/3/2005
ckniffin: 4/14/2005
terry: 2/22/2005
tkritzer: 10/5/2004
terry: 9/30/2004
alopez: 6/15/2004
tkritzer: 5/18/2004
terry: 5/12/2004
alopez: 4/2/2004
tkritzer: 3/25/2004
ckniffin: 3/25/2004
alopez: 10/29/2003
terry: 10/29/2003
terry: 7/24/2003
tkritzer: 7/24/2003
tkritzer: 7/22/2003
terry: 7/14/2003
cwells: 7/14/2003
carol: 6/12/2003
ckniffin: 6/9/2003
tkritzer: 6/5/2003
terry: 5/30/2003
tkritzer: 5/15/2003
ckniffin: 4/28/2003
mgross: 3/19/2003
terry: 3/14/2003
tkritzer: 2/4/2003
terry: 2/3/2003
ckniffin: 1/31/2003
carol: 1/31/2003
ckniffin: 1/30/2003
cwells: 1/14/2003
ckniffin: 1/9/2003
cwells: 1/2/2003
terry: 12/27/2002
ckniffin: 12/16/2002
carol: 11/7/2002
tkritzer: 11/6/2002
tkritzer: 11/5/2002
tkritzer: 10/2/2002
tkritzer: 10/1/2002
carol: 8/28/2002
terry: 8/28/2002
carol: 7/8/2002
alopez: 5/22/2002
terry: 5/17/2002
alopez: 4/12/2002
mgross: 3/29/2002
terry: 3/28/2002
terry: 3/21/2002
mgross: 3/11/2002
terry: 3/5/2002
cwells: 2/18/2002
cwells: 2/13/2002
mgross: 2/13/2002
mgross: 2/12/2002
mcapotos: 1/9/2002
terry: 1/4/2002
carol: 11/29/2001
mcapotos: 11/26/2001
terry: 11/9/2001
cwells: 10/30/2001
mcapotos: 1/25/2001
mcapotos: 1/23/2001
terry: 1/16/2001
alopez: 9/20/2000
terry: 9/19/2000
mcapotos: 8/8/2000
alopez: 4/25/2000
alopez: 4/13/2000
terry: 4/13/2000
mcapotos: 3/17/2000
mcapotos: 3/7/2000
terry: 2/24/2000
alopez: 12/27/1999
terry: 12/22/1999
carol: 12/9/1999
carol: 9/22/1999
jlewis: 9/16/1999
terry: 9/8/1999
kayiaros: 7/13/1999
carol: 3/7/1999
terry: 3/2/1999
carol: 1/18/1999
terry: 1/6/1999
dkim: 12/18/1998
carol: 11/15/1998
terry: 11/5/1998
alopez: 9/16/1998
terry: 9/15/1998
dkim: 9/11/1998
dholmes: 7/22/1998
terry: 6/26/1998
terry: 6/3/1998
alopez: 6/1/1998
terry: 5/27/1998
terry: 5/21/1998
carol: 5/16/1998
carol: 5/12/1998
terry: 5/5/1998
joanna: 12/17/1997
terry: 11/11/1997
terry: 9/16/1997
terry: 9/10/1997
terry: 9/9/1997
terry: 9/4/1997
mark: 8/25/1997
terry: 8/12/1997
terry: 6/23/1997
terry: 6/20/1997
mark: 6/9/1997
alopez: 5/8/1997
mark: 2/28/1997
terry: 2/26/1997
mark: 11/20/1996
terry: 11/12/1996
terry: 8/27/1996
terry: 7/15/1996
mark: 7/11/1996
carol: 7/3/1996
terry: 7/1/1996
terry: 6/20/1996
mark: 6/19/1996
terry: 6/11/1996
mark: 5/21/1996
terry: 5/17/1996
terry: 5/14/1996
mark: 4/25/1996
mark: 4/23/1996
mark: 4/22/1996
mark: 4/19/1996
terry: 4/17/1996
terry: 4/15/1996
terry: 4/1/1996
terry: 3/22/1996
mark: 3/9/1996
terry: 3/1/1996
mark: 2/10/1996
terry: 2/7/1996
mark: 1/30/1996
terry: 1/24/1996
mark: 12/13/1995
mark: 11/14/1995
carol: 3/3/1995
mimadm: 11/5/1994
jason: 7/25/1994
warfield: 4/12/1994

RBCC Red Blood Cell Collection

Full text data of SOD1