RBCC Red Blood Cell Collection

DCTN1 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Dynactin subunit 1 (150 kDa dynein-associated polypeptide; DAP-150; DP-150; p135; p150-glued)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q14203
ID DCTN1_HUMAN Reviewed; 1278 AA.
AC Q14203; A8MY36; B4DM45; E9PFS5; E9PGE1; G5E9H4; O95296; Q6IQ37;
read moreAC Q9BRM9; Q9UIU1; Q9UIU2;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 18-OCT-2001, sequence version 3.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Dynactin subunit 1;
DE AltName: Full=150 kDa dynein-associated polypeptide;
DE AltName: Full=DAP-150;
DE Short=DP-150;
DE AltName: Full=p135;
DE AltName: Full=p150-glued;
GN Name=DCTN1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=9799602; DOI=10.1006/geno.1998.5542;
RA Collin G.B., Nishina P.M., Marshall J.D., Naggert J.K.;
RT "Human DCTN1: genomic structure and evaluation as a candidate for
RT Alstrom syndrome.";
RL Genomics 53:359-364(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4).
RC TISSUE=Brain, and Trachea;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC TISSUE=Brain;
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 [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 9-1278.
RC TISSUE=Brain;
RX PubMed=8838327; DOI=10.1006/geno.1996.0068;
RA Holzbaur E.L.F., Tokito M.K.;
RT "Localization of the DCTN1 gene encoding p150Glued to human chromosome
RT 2p13 by fluorescence in situ hybridization.";
RL Genomics 31:398-399(1996).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-1278 (ISOFORM 6), AND ALTERNATIVE
RP SPLICING.
RC TISSUE=Brain;
RX PubMed=8856662; DOI=10.1091/mbc.7.8.1167;
RA Tokito M.K., Howland D.S., Lee V.M.-Y., Holzbaur E.L.F.;
RT "Functionally distinct isoforms of dynactin are expressed in human
RT neurons.";
RL Mol. Biol. Cell 7:1167-1180(1996).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 18-1278.
RX PubMed=9805007; DOI=10.1016/S0167-4781(98)00195-X;
RA Tokito M.K., Holzbaur E.L.F.;
RT "The genomic structure of DCTN1, a candidate gene for limb-girdle
RT muscular dystrophy.";
RL Biochim. Biophys. Acta 1442:432-436(1998).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1081-1278.
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 (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP INTERACTION WITH MAPRE1; MAPRE2 AND MAPRE3.
RX PubMed=14514668; DOI=10.1074/jbc.M306194200;
RA Bu W., Su L.-K.;
RT "Characterization of functional domains of human EB1 family
RT proteins.";
RL J. Biol. Chem. 278:49721-49731(2003).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP UBIQUITINATION, AND INTERACTION WITH FBXL5.
RX PubMed=17532294; DOI=10.1016/j.bbrc.2007.05.068;
RA Zhang N., Liu J., Ding X., Aikhionbare F., Jin C., Yao X.;
RT "FBXL5 interacts with p150Glued and regulates its ubiquitination.";
RL Biochem. Biophys. Res. Commun. 359:34-39(2007).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP INTERACTION WITH SNX6.
RX PubMed=19935774; DOI=10.1038/cr.2009.130;
RA Hong Z., Yang Y., Zhang C., Niu Y., Li K., Zhao X., Liu J.J.;
RT "The retromer component SNX6 interacts with dynactin p150(Glued) and
RT mediates endosome-to-TGN transport.";
RL Cell Res. 19:1334-1349(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-108, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
RP INTERACTION WITH ECM29.
RX PubMed=20682791; DOI=10.1074/jbc.M110.154120;
RA Gorbea C., Pratt G., Ustrell V., Bell R., Sahasrabudhe S.,
RA Hughes R.E., Rechsteiner M.;
RT "A protein interaction network for Ecm29 links the 26 S proteasome to
RT molecular motors and endosomal components.";
RL J. Biol. Chem. 285:31616-31633(2010).
RN [17]
RP INTERACTION WITH DYNAP.
RX PubMed=20978158; DOI=10.1158/1535-7163.MCT-10-0730;
RA Kunoh T., Noda T., Koseki K., Sekigawa M., Takagi M., Shin-ya K.,
RA Goshima N., Iemura S., Natsume T., Wada S., Mukai Y., Ohta S.,
RA Sasaki R., Mizukami T.;
RT "A novel human dynactin-associated protein, dynAP, promotes activation
RT of Akt, and ergosterol-related compounds induce dynAP-dependent
RT apoptosis of human cancer cells.";
RL Mol. Cancer Ther. 9:2934-2942(2010).
RN [18]
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 [19]
RP INTERACTION WITH CLN3.
RX PubMed=22261744; DOI=10.1007/s00018-011-0913-1;
RA Uusi-Rauva K., Kyttala A., van der Kant R., Vesa J., Tanhuanpaa K.,
RA Neefjes J., Olkkonen V.M., Jalanko A.;
RT "Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor
RT proteins and modifies location of late endosomal compartments.";
RL Cell. Mol. Life Sci. 69:2075-2089(2012).
RN [20]
RP INTERACTION WITH MISP.
RX PubMed=23509069; DOI=10.1083/jcb.201207050;
RA Zhu M., Settele F., Kotak S., Sanchez-Pulido L., Ehret L.,
RA Ponting C.P., Goenczy P., Hoffmann I.;
RT "MISP is a novel Plk1 substrate required for proper spindle
RT orientation and mitotic progression.";
RL J. Cell Biol. 200:773-787(2013).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 15-107 IN COMPLEX WITH
RP MAPRE1, AND INTERACTION WITH MAPRE1.
RX PubMed=16109370; DOI=10.1016/j.molcel.2005.06.034;
RA Hayashi I., Wilde A., Mal T.K., Ikura M.;
RT "Structural basis for the activation of microtubule assembly by the
RT EB1 and p150Glued complex.";
RL Mol. Cell 19:449-460(2005).
RN [22]
RP STRUCTURE BY NMR OF 1-99.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the CAP-Gly domain in human dynactin 1.";
RL Submitted (NOV-2005) to the PDB data bank.
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 18-111 IN COMPLEX WITH
RP MAPRE1, AND INTERACTION WITH MAPRE1.
RX PubMed=16949363; DOI=10.1016/j.molcel.2006.07.013;
RA Honnappa S., Okhrimenko O., Jaussi R., Jawhari H., Jelesarov I.,
RA Winkler F.K., Steinmetz M.O.;
RT "Key interaction modes of dynamic +TIP networks.";
RL Mol. Cell 23:663-671(2006).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 15-111 IN COMPLEX WITH
RP CLIP1, SUBCELLULAR LOCATION, AND INTERACTION WITH CLIP1.
RX PubMed=17828277; DOI=10.1038/nsmb1291;
RA Weisbrich A., Honnappa S., Jaussi R., Okhrimenko O., Frey D.,
RA Jelesarov I., Akhmanova A., Steinmetz M.O.;
RT "Structure-function relationship of CAP-Gly domains.";
RL Nat. Struct. Mol. Biol. 14:959-967(2007).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 15-107 IN COMPLEX WITH
RP CLIP1, INTERACTION WITH CLIP1, AND MUTAGENESIS OF LYS-68 AND ARG-90.
RX PubMed=17828275; DOI=10.1038/nsmb1299;
RA Hayashi I., Plevin M.J., Ikura M.;
RT "CLIP170 autoinhibition mimics intermolecular interactions with
RT p150Glued or EB1.";
RL Nat. Struct. Mol. Biol. 14:980-981(2007).
RN [26]
RP VARIANT HMN7B SER-59.
RX PubMed=12627231; DOI=10.1038/ng1123;
RA Puls I., Jonnakuty C., LaMonte B.H., Holzbaur E.L., Tokito M.,
RA Mann E., Floeter M.K., Bidus K., Drayna D., Oh S.J., Brown R.H. Jr.,
RA Ludlow C.L., Fischbeck K.H.;
RT "Mutant dynactin in motor neuron disease.";
RL Nat. Genet. 33:455-456(2003).
RN [27]
RP VARIANTS SUSCEPTIBILITY TO ALS THR-571; TRP-785 AND ILE-1249.
RX PubMed=15326253;
RA Muench C., Sedlmeier R., Meyer T., Homberg V., Sperfeld A.D., Kurt A.,
RA Prudlo J., Peraus G., Hanemann C.O., Stumm G., Ludolph A.C.;
RT "Point mutations of the p150 subunit of dynactin (DCTN1) gene in
RT ALS.";
RL Neurology 63:724-726(2004).
RN [28]
RP VARIANT SUSCEPTIBILITY TO ALS LYS-1101.
RX PubMed=16240349; DOI=10.1002/ana.20631;
RA Muench C., Rosenbohm A., Sperfeld A.-D., Uttner I., Reske S.,
RA Krause B.J., Sedlmeier R., Meyer T., Hanemann C.O., Stumm G.,
RA Ludolph A.C.;
RT "Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS
RT and FTD.";
RL Ann. Neurol. 58:777-780(2005).
RN [29]
RP CHARACTERIZATION OF VARIANT HMN7B SER-59.
RX PubMed=16505168; DOI=10.1083/jcb.200511068;
RA Levy J.R., Sumner C.J., Caviston J.P., Tokito M.K., Ranganathan S.,
RA Ligon L.A., Wallace K.E., LaMonte B.H., Harmison G.G., Puls I.,
RA Fischbeck K.H., Holzbaur E.L.F.;
RT "A motor neuron disease-associated mutation in p150Glued perturbs
RT dynactin function and induces protein aggregation.";
RL J. Cell Biol. 172:733-745(2006).
RN [30]
RP VARIANTS PERRYS ARG-71; GLU-71; ALA-71; PRO-72 AND PRO-74,
RP CHARACTERIZATION OF VARIANTS PERRYS ARG-71 AND PRO-74, AND
RP CHARACTERIZATION OF VARIANT HMN7B SER-59.
RX PubMed=19136952; DOI=10.1038/ng.293;
RA Farrer M.J., Hulihan M.M., Kachergus J.M., Daechsel J.C.,
RA Stoessl A.J., Grantier L.L., Calne S., Calne D.B., Lechevalier B.,
RA Chapon F., Tsuboi Y., Yamada T., Gutmann L., Elibol B., Bhatia K.P.,
RA Wider C., Vilarino-Gueell C., Ross O.A., Brown L.A.,
RA Castanedes-Casey M., Dickson D.W., Wszolek Z.K.;
RT "DCTN1 mutations in Perry syndrome.";
RL Nat. Genet. 41:163-165(2009).
RN [31]
RP VARIANT ILE-1249.
RX PubMed=19506225; DOI=10.1212/WNL.0b013e3181a92c4c;
RA Vilarino-Gueell C., Wider C., Soto-Ortolaza A.I., Cobb S.A.,
RA Kachergus J.M., Keeling B.H., Dachsel J.C., Hulihan M.M.,
RA Dickson D.W., Wszolek Z.K., Uitti R.J., Graff-Radford N.R.,
RA Boeve B.F., Josephs K.A., Miller B., Boylan K.B., Gwinn K.,
RA Adler C.H., Aasly J.O., Hentati F., Destee A., Krygowska-Wajs A.,
RA Chartier-Harlin M.-C., Ross O.A., Rademakers R., Farrer M.J.;
RT "Characterization of DCTN1 genetic variability in neurodegeneration.";
RL Neurology 72:2024-2028(2009).
RN [32]
RP CHARACTERIZATION OF VARIANT HMN7B SER-59.
RX PubMed=19279216; DOI=10.1073/pnas.0810828106;
RA Moore J.K., Sept D., Cooper J.A.;
RT "Neurodegeneration mutations in dynactin impair dynein-dependent
RT nuclear migration.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:5147-5152(2009).
CC -!- FUNCTION: Required for the cytoplasmic dynein-driven retrograde
CC movement of vesicles and organelles along microtubules. Dynein-
CC dynactin interaction is a key component of the mechanism of axonal
CC transport of vesicles and organelles.
CC -!- SUBUNIT: Large macromolecular complex of at least 10 components;
CC p150(glued) binds directly to microtubules and to cytoplasmic
CC dynein. Interacts with the C-terminus of MAPRE1, MAPRE2 and
CC MAPRE3. Interacts (via C-terminus) with SNX6. Interacts with
CC CLIP1, CLN3, DYNAP, ECM29 and FBXL5. Interacts with MISP; this
CC interaction regulates its distribution at the cell cortex.
CC -!- INTERACTION:
CC Q96RK4:BBS4; NbExp=3; IntAct=EBI-724352, EBI-1805814;
CC P10636-8:MAPT; NbExp=8; IntAct=EBI-724352, EBI-366233;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton.
CC Note=Colocalizes with microtubules.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=p150;
CC IsoId=Q14203-1; Sequence=Displayed;
CC Name=p135;
CC IsoId=Q14203-2; Sequence=VSP_000760;
CC Name=3;
CC IsoId=Q14203-3; Sequence=VSP_045392, VSP_045393, VSP_045394;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q14203-4; Sequence=VSP_045393, VSP_045394;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q14203-5; Sequence=VSP_000760, VSP_045394;
CC Note=No experimental confirmation available;
CC Name=6;
CC IsoId=Q14203-6; Sequence=VSP_047174;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Brain.
CC -!- PTM: Ubiquitinated by a SCF complex containing FBXL5, leading to
CC its degradation by the proteasome.
CC -!- DISEASE: Neuronopathy, distal hereditary motor, 7B (HMN7B)
CC [MIM:607641]: A neuromuscular disorder. Distal hereditary motor
CC neuronopathies constitute a heterogeneous group of neuromuscular
CC disorders caused by selective degeneration of motor neurons in the
CC anterior horn of the spinal cord, without sensory deficit in the
CC posterior horn. The overall clinical picture consists of a
CC classical distal muscular atrophy syndrome in the legs without
CC clinical sensory loss. The disease starts with weakness and
CC wasting of distal muscles of the anterior tibial and peroneal
CC compartments of the legs. Later on, weakness and atrophy may
CC expand to the proximal muscles of the lower limbs and/or to the
CC distal upper limbs. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Amyotrophic lateral sclerosis (ALS) [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=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry.
CC -!- DISEASE: Perry syndrome (PERRYS) [MIM:168605]: A neuropsychiatric
CC disorder characterized by mental depression not responsive to
CC antidepressant drugs or electroconvulsive therapy, sleep
CC disturbances, exhaustion and marked weight loss. Parkinsonism
CC develops later and respiratory failure occurred terminally.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the dynactin 150 kDa subunit family.
CC -!- SIMILARITY: Contains 1 CAP-Gly domain.
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DR EMBL; AF064205; AAD55811.1; -; Genomic_DNA.
DR EMBL; AF064203; AAD55811.1; JOINED; Genomic_DNA.
DR EMBL; AF064204; AAD55811.1; JOINED; Genomic_DNA.
DR EMBL; AF064205; AAD55812.1; -; Genomic_DNA.
DR EMBL; AF064204; AAD55812.1; JOINED; Genomic_DNA.
DR EMBL; AK297286; BAG59757.1; -; mRNA.
DR EMBL; AK314352; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC005041; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471053; EAW99684.1; -; Genomic_DNA.
DR EMBL; BC071583; AAH71583.1; -; mRNA.
DR EMBL; X98801; CAA67333.1; -; mRNA.
DR EMBL; AF086947; AAD03694.1; -; Genomic_DNA.
DR EMBL; AF086927; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086928; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086929; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086930; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086931; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086932; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086933; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086934; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086935; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086936; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086937; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086938; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086939; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086940; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086941; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086942; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086943; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086944; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086945; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; AF086946; AAD03694.1; JOINED; Genomic_DNA.
DR EMBL; BT006758; AAP35404.1; -; mRNA.
DR RefSeq; NP_001128512.1; NM_001135040.2.
DR RefSeq; NP_001128513.1; NM_001135041.2.
DR RefSeq; NP_001177765.1; NM_001190836.1.
DR RefSeq; NP_001177766.1; NM_001190837.1.
DR RefSeq; NP_004073.2; NM_004082.4.
DR RefSeq; NP_075408.1; NM_023019.3.
DR UniGene; Hs.516111; -.
DR PDB; 1TXQ; X-ray; 1.80 A; A=15-107.
DR PDB; 2COY; NMR; -; A=1-99.
DR PDB; 2HKN; X-ray; 1.87 A; A/B=18-111.
DR PDB; 2HKQ; X-ray; 1.86 A; B=18-111.
DR PDB; 2HL3; X-ray; 2.03 A; A/B=18-111.
DR PDB; 2HL5; X-ray; 1.93 A; C/D=18-111.
DR PDB; 2HQH; X-ray; 1.80 A; A/B/C/D=15-107.
DR PDB; 3E2U; X-ray; 2.60 A; A/B/C/D=15-111.
DR PDB; 3TQ7; X-ray; 2.30 A; P/Q=27-97.
DR PDBsum; 1TXQ; -.
DR PDBsum; 2COY; -.
DR PDBsum; 2HKN; -.
DR PDBsum; 2HKQ; -.
DR PDBsum; 2HL3; -.
DR PDBsum; 2HL5; -.
DR PDBsum; 2HQH; -.
DR PDBsum; 3E2U; -.
DR PDBsum; 3TQ7; -.
DR ProteinModelPortal; Q14203; -.
DR SMR; Q14203; 25-98.
DR DIP; DIP-31365N; -.
DR IntAct; Q14203; 38.
DR MINT; MINT-5004548; -.
DR STRING; 9606.ENSP00000354791; -.
DR PhosphoSite; Q14203; -.
DR DMDM; 17375490; -.
DR OGP; Q14203; -.
DR PaxDb; Q14203; -.
DR PRIDE; Q14203; -.
DR DNASU; 1639; -.
DR Ensembl; ENST00000361874; ENSP00000354791; ENSG00000204843.
DR Ensembl; ENST00000394003; ENSP00000377571; ENSG00000204843.
DR Ensembl; ENST00000407639; ENSP00000384844; ENSG00000204843.
DR Ensembl; ENST00000409240; ENSP00000386406; ENSG00000204843.
DR Ensembl; ENST00000409438; ENSP00000387270; ENSG00000204843.
DR Ensembl; ENST00000409567; ENSP00000386843; ENSG00000204843.
DR GeneID; 1639; -.
DR KEGG; hsa:1639; -.
DR UCSC; uc002skw.2; human.
DR CTD; 1639; -.
DR GeneCards; GC02M074588; -.
DR H-InvDB; HIX0204314; -.
DR HGNC; HGNC:2711; DCTN1.
DR HPA; CAB009108; -.
DR MIM; 105400; phenotype.
DR MIM; 168605; phenotype.
DR MIM; 601143; gene.
DR MIM; 607641; phenotype.
DR neXtProt; NX_Q14203; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 139589; Distal hereditary motor neuropathy type 7.
DR Orphanet; 178509; Perry syndrome.
DR PharmGKB; PA27180; -.
DR eggNOG; COG5244; -.
DR HOGENOM; HOG000015352; -.
DR HOVERGEN; HBG004956; -.
DR KO; K04648; -.
DR OMA; SAQLMEQ; -.
DR OrthoDB; EOG79W94B; -.
DR PhylomeDB; Q14203; -.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; DCTN1; human.
DR EvolutionaryTrace; Q14203; -.
DR GeneWiki; DCTN1; -.
DR GenomeRNAi; 1639; -.
DR NextBio; 6734; -.
DR PMAP-CutDB; Q14203; -.
DR PRO; PR:Q14203; -.
DR ArrayExpress; Q14203; -.
DR Bgee; Q14203; -.
DR CleanEx; HS_DCTN1; -.
DR Genevestigator; Q14203; -.
DR GO; GO:0031252; C:cell leading edge; IEA:Ensembl.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005869; C:dynactin complex; IEA:InterPro.
DR GO; GO:0030286; C:dynein complex; IEA:UniProtKB-KW.
DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0000922; C:spindle pole; IDA:UniProtKB.
DR GO; GO:0003774; F:motor activity; IEA:UniProtKB-KW.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0010970; P:microtubule-based transport; IEA:InterPro.
DR GO; GO:0007067; P:mitosis; NAS:ProtInc.
DR GO; GO:0007399; P:nervous system development; NAS:UniProtKB.
DR Gene3D; 2.30.30.190; -; 1.
DR InterPro; IPR000938; CAP-Gly_domain.
DR InterPro; IPR027663; DCTN1.
DR InterPro; IPR022157; Dynactin.
DR PANTHER; PTHR18916:SF26; PTHR18916:SF26; 1.
DR Pfam; PF01302; CAP_GLY; 1.
DR Pfam; PF12455; Dynactin; 1.
DR SMART; SM01052; CAP_GLY; 1.
DR SUPFAM; SSF74924; SSF74924; 1.
DR PROSITE; PS00845; CAP_GLY_1; 1.
DR PROSITE; PS50245; CAP_GLY_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis;
KW Coiled coil; Complete proteome; Cytoplasm; Cytoskeleton; Dynein;
KW Microtubule; Neurodegeneration; Parkinsonism; Phosphoprotein;
KW Polymorphism; Reference proteome; Transport; Ubl conjugation.
FT CHAIN 1 1278 Dynactin subunit 1.
FT /FTId=PRO_0000083518.
FT DOMAIN 48 90 CAP-Gly.
FT COILED 213 547 Potential.
FT COILED 943 1049 Potential.
FT COILED 1182 1211 Potential.
FT COMPBIAS 164 191 Ser-rich.
FT MOD_RES 108 108 Phosphothreonine.
FT VAR_SEQ 1 138 MAQSKRHVYSRTPSGSRMSAEASARPLRVGSRVEVIGKGHR
FT GTVAYVGATLFATGKWVGVILDEAKGKNDGTVQGRKYFTCD
FT EGHGIFVRQSQIQVFEDGADTTSPETPDSSASKVLKREGTD
FT TTAKTSKLRGLKPKK -> MMRQ (in isoform p135
FT and isoform 5).
FT /FTId=VSP_000760.
FT VAR_SEQ 1 17 Missing (in isoform 3).
FT /FTId=VSP_045392.
FT VAR_SEQ 132 151 Missing (in isoform 3 and isoform 4).
FT /FTId=VSP_045393.
FT VAR_SEQ 132 138 Missing (in isoform 6).
FT /FTId=VSP_047174.
FT VAR_SEQ 1066 1070 Missing (in isoform 3, isoform 4 and
FT isoform 5).
FT /FTId=VSP_045394.
FT VARIANT 59 59 G -> S (in HMN7B; shows a modestly
FT reduced affinity for microtubules which
FT has been suggested to impair axonal
FT transport; the effect is identical to
FT that of complete loss of the CAP-Gly
FT domain).
FT /FTId=VAR_015850.
FT VARIANT 71 71 G -> A (in PERRYS).
FT /FTId=VAR_063867.
FT VARIANT 71 71 G -> E (in PERRYS).
FT /FTId=VAR_063868.
FT VARIANT 71 71 G -> R (in PERRYS; diminishes microtubule
FT binding and lead to intracytoplasmic
FT inclusions).
FT /FTId=VAR_063869.
FT VARIANT 72 72 T -> P (in PERRYS).
FT /FTId=VAR_063870.
FT VARIANT 74 74 Q -> P (in PERRYS; diminishes microtubule
FT binding and lead to intracytoplasmic
FT inclusions).
FT /FTId=VAR_063871.
FT VARIANT 163 163 A -> P.
FT /FTId=VAR_001373.
FT VARIANT 287 287 L -> M (in dbSNP:rs13420401).
FT /FTId=VAR_048677.
FT VARIANT 495 495 R -> Q (in dbSNP:rs17721059).
FT /FTId=VAR_048678.
FT VARIANT 571 571 M -> T (in susceptibility to amyotrophic
FT lateral sclerosis).
FT /FTId=VAR_063872.
FT VARIANT 785 785 R -> W (in susceptibility to amyotrophic
FT lateral sclerosis).
FT /FTId=VAR_063873.
FT VARIANT 1101 1101 R -> K (in susceptibility to amyotrophic
FT lateral sclerosis).
FT /FTId=VAR_063874.
FT VARIANT 1249 1249 T -> I (in susceptibility to amyotrophic
FT lateral sclerosis; unknown pathological
FT significance; dbSNP:rs72466496).
FT /FTId=VAR_063875.
FT MUTAGEN 68 68 K->A: Abolishes interaction with CLIP1.
FT MUTAGEN 90 90 R->E: Abolishes interaction with CLIP1.
FT CONFLICT 10 10 S -> N (in Ref. 7; CAA67333).
FT CONFLICT 257 257 Q -> R (in Ref. 2; BAG59757).
FT CONFLICT 349 349 K -> R (in Ref. 2; AK314352).
FT CONFLICT 368 368 A -> V (in Ref. 2; AK314352).
FT CONFLICT 526 526 H -> N (in Ref. 5; AAH71583).
FT CONFLICT 618 618 K -> R (in Ref. 5; AAH71583).
FT CONFLICT 712 712 D -> V (in Ref. 7; CAA67333).
FT CONFLICT 1081 1081 V -> M (in Ref. 9; AAP35404).
FT CONFLICT 1261 1261 R -> Q (in Ref. 2; BAG59757).
FT CONFLICT 1274 1274 S -> I (in Ref. 5; AAH71583).
FT STRAND 17 19
FT STRAND 32 35
FT TURN 36 38
FT STRAND 41 48
FT STRAND 51 55
FT STRAND 57 65
FT STRAND 67 73
FT STRAND 76 78
FT TURN 83 85
FT STRAND 86 89
FT HELIX 91 93
FT STRAND 94 96
SQ SEQUENCE 1278 AA; 141695 MW; 6DCEA5E67856E4BC CRC64;
MAQSKRHVYS RTPSGSRMSA EASARPLRVG SRVEVIGKGH RGTVAYVGAT LFATGKWVGV
ILDEAKGKND GTVQGRKYFT CDEGHGIFVR QSQIQVFEDG ADTTSPETPD SSASKVLKRE
GTDTTAKTSK LRGLKPKKAP TARKTTTRRP KPTRPASTGV AGASSSLGPS GSASAGELSS
SEPSTPAQTP LAAPIIPTPV LTSPGAVPPL PSPSKEEEGL RAQVRDLEEK LETLRLKRAE
DKAKLKELEK HKIQLEQVQE WKSKMQEQQA DLQRRLKEAR KEAKEALEAK ERYMEEMADT
ADAIEMATLD KEMAEERAES LQQEVEALKE RVDELTTDLE ILKAEIEEKG SDGAASSYQL
KQLEEQNARL KDALVRMRDL SSSEKQEHVK LQKLMEKKNQ ELEVVRQQRE RLQEELSQAE
STIDELKEQV DAALGAEEMV EMLTDRNLNL EEKVRELRET VGDLEAMNEM NDELQENARE
TELELREQLD MAGARVREAQ KRVEAAQETV ADYQQTIKKY RQLTAHLQDV NRELTNQQEA
SVERQQQPPP ETFDFKIKFA ETKAHAKAIE MELRQMEVAQ ANRHMSLLTA FMPDSFLRPG
GDHDCVLVLL LMPRLICKAE LIRKQAQEKF ELSENCSERP GLRGAAGEQL SFAAGLVYSL
SLLQATLHRY EHALSQCSVD VYKKVGSLYP EMSAHERSLD FLIELLHKDQ LDETVNVEPL
TKAIKYYQHL YSIHLAEQPE DCTMQLADHI KFTQSALDCM SVEVGRLRAF LQGGQEATDI
ALLLRDLETS CSDIRQFCKK IRRRMPGTDA PGIPAALAFG PQVSDTLLDC RKHLTWVVAV
LQEVAAAAAQ LIAPLAENEG LLVAALEELA FKASEQIYGT PSSSPYECLR QSCNILISTM
NKLATAMQEG EYDAERPPSK PPPVELRAAA LRAEITDAEG LGLKLEDRET VIKELKKSLK
IKGEELSEAN VRLSLLEKKL DSAAKDADER IEKVQTRLEE TQALLRKKEK EFEETMDALQ
ADIDQLEAEK AELKQRLNSQ SKRTIEGLRG PPPSGIATLV SGIAGEEQQR GAIPGQAPGS
VPGPGLVKDS PLLLQQISAM RLHISQLQHE NSILKGAQMK ASLASLPPLH VAKLSHEGPG
SELPAGALYR KTSQLLETLN QLSTHTHVVD ITRTSPAAKS PSAQLMEQVA QLKSLSDTVE
KLKDEVLKET VSQRPGATVP TDFATFPSSA FLRAKEEQQD DTVYMGKVTF SCAAGFGQRH
RLVLTQEQLH QLHSRLIS
//

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.

*FIELD* SA
Engel (1976); Gimenez-Roldan and Esteban (1977); Haberlandt (1961);
Hirano et al. (1967); Phillips et al. (1978); Swerts and Van den Bergh
(1976); Takahashi et al. (1972)
*FIELD* RF
1. Al-Chalabi, A.; Andersen, P. M.; Chioza, B.; Shaw, C.; Sham, P.
C.; Robberecht, W.; Matthijs, G.; Camu, W.; Marklund, S. L.; Forsgren,
L.; Rouleau, G.; Laing, N. G.; Hurse, P. V.; Siddique, T.; Leigh,
P. N.; Powell, J. F.: Recessive amyotrophic lateral sclerosis families
with the D90A SOD1 mutation share a common founder: evidence for a
linked protective factor. Hum. Molec. Genet. 7: 2045-2050, 1998.

2. Alberca, R.; Castilla, J. M.; Gil-Peralta, A.: Hereditary amyotrophic
lateral sclerosis. J. Neurol. Sci. 50: 201-206, 1981.

3. Albom, M.: Tuesdays with Morrie: an old man, a young man, and
the last great lesson. New York: Doubleday , 1997. P. 162.

4. Alter, M.; Schaumann, B.: Hereditary amyotrophic lateral sclerosis:
a report of two families. Europ. Neurol. 14: 250-265, 1976.

5. Amick, L. D.; Nelson, J. W.; Zellweger, H.: Familial motor neuron
disease, non-Chamorro type: report of kinship. Acta Neurol. Scand. 47:
341-349, 1971.

6. Andersen, P. M.; Nilsson, P.; Ala-Hurula, V.; Keranen, M.-L.; Tarvainen,
I.; Haltia, T.; Nilsson, L.; Binzer, M.; Forsgren, L.; Marklund, S.
L.: Amyotrophic lateral sclerosis associated with homozygosity for
an asp90-to-ala mutation in CuZn-superoxide dismutase. Nature Genet. 10:
61-66, 1995.

7. Armakola, M.; Higgins, M. J.; Figley, M. D.; Barmada, S. J.; Scarborough,
E. A.; Diaz, Z.; Fang, X.; Shorter, J.; Krogan, N. J.; Finkbeiner,
S.; Farese, R. V., Jr.; Gitler, A. D.: Inhibition of RNA lariat debranching
enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genet. 44:
1302-1309, 2012.

8. Askanas, V.; Wojcik, S.; Engel, W. K.: Expression of Nogo-A in
human muscle fibers is not specific for amyotrophic lateral sclerosis.
(Letter) Ann. Neurol. 62: 676-677, 2007.

9. Awano, T.; Johnson, G. S.; Wade, C. M.; Katz, M. L.; Johnson, G.
C.; Taylor, J. F.; Perloski, M.; Biagi, T.; Baranowska, I.; Long,
S.; March, P. A.; Olby, N. J.; Shelton, G. D.; Khan, S.; O'Brien,
D. P.; Lindblad-Toh, K.; Coates, J. R.: Genome-wide association analysis
reveals a SOD1 mutation in canine degenerative myelopathy that resembles
amyotrophic lateral sclerosis. Proc. Nat. Acad. Sci. 106: 2794-2799,
2009.

10. Azzouz, M.; Ralph, G. S.; Storkebaum, E.; Walmsley, L. E.; Mitrophanous,
K. A.; Kingsman, S. M.; Carmeliet, P.; Mazarakis, N. D.: VEGF delivery
with retrogradely transported lentivector prolongs survival in a mouse
ALS model. Nature 429: 413-417, 2004.

11. Blauw, H. M.; Barnes, C. P.; van Vught, P. W. J.; van Rheenen,
W.; Verheul, M.; Cuppen, E.; Veldink, J. H.; van den Berg, L. H.:
SMN1 gene duplications are associated with sporadic ALS. Neurology 78:
776-780, 2012.

12. Boillee, S.; Yamanaka, K.; Lobsiger, C. S.; Copeland, N. G.; Jenkins,
N. A.; Kassiotis, G.; Kollias, G.; Cleveland, D. W.: Onset and progression
in inherited ALS determined by motor neurons and microglia. Science 312:
1389-1392, 2006.

13. Bordet, T.; Lesbordes, J.-C.; Rouhani, S.; Castelnau-Ptakhine,
L.; Schmalbruch, H.; Haase, G.; Kahn, A.: Protective effects of cardiotrophin-1
adenoviral gene transfer on neuromuscular degeneration in transgenic
ALS mice. Hum. Molec. Genet. 10: 1925-1933, 2001.

14. Boulis, N. M.; Willmarth, N. E.; Song, D. K.; Feldman, E. L.;
Imperiale, M. J.: Intraneural colchicine inhibition of adenoviral
and adeno-associated viral vector remote spinal cord gene delivery. Neurosurgery 52:
381-387, 2003.

15. Bradley, M.; Bradley, L.; de Belleroche, J.; Orrell, R. W.: Patterns
of inheritance in familial ALS. Neurology 64: 1628-1631, 2005.

16. Bradley, W. G.; Krasin, F.: A new hypothesis of the etiology
of amyotrophic lateral sclerosis: the DNA hypothesis. Arch. Neurol. 39:
677-680, 1982.

17. Broom, W. J.; Parton, M. J.; Vance, C. A.; Russ, C.; Andersen,
P. M.; Hansen, V.; Leigh, P. N.; Powell, J. F.; Al-Chalabi, A.; Shaw,
C. E.: No association of the SOD1 locus and disease susceptibility
or phenotype in sporadic ALS. Neurology 63: 2419-2422, 2004.

18. Brown, M. R.: 'Wetherbee ail': the inheritance of progressive
muscular atrophy as a dominant trait in two New England families. New
Eng. J. Med. 245: 645-647, 1951.

19. Brown, M. R.: The inheritance of progressive muscular atrophy
as a dominant trait in two New England families. New Eng. J. Med. 262:
1280-1282, 1960.

20. Chio, A.; Traynor, B. J.; Lombardo, F.; Fimognari, M.; Calvo,
A.; Ghiglione, P.; Mutani, R.; Restagno, G.: Prevalence of SOD1 mutations
in the Italian ALS population. Neurology 70: 533-537, 2008.

21. Corcia, P.; Camu, W.; Halimi, J.-M.; Vourc'h, P.; Antar, C.; Vedrine,
S.; Giraudeau, B.; de Toffol, B.; Andres, C. R.; the French ALS Research
Group: SMN1 gene, but not SMN2, is a risk factor for sporadic ALS. Neurology 67:
1147-1150, 2006.

22. Corcia, P.; Mayeux-Portas, V.; Khoris, J.; de Toffol, B.; Autret,
A.; Muh, J.-P.; Camu, W.; Andres, C.; the French ALS Research Group
: Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic
lateral sclerosis. Ann. Neurol. 51: 243-246, 2002.

23. Cudkowicz, M. E.; McKenna-Yasek, D.; Sapp, P. E.; Chin, W.; Geller,
B.; Hayden, D. L.; Schoenfeld, D. A.; Hosler, B. A.; Horvitz, H. R.;
Brown, R. H.: Epidemiology of mutations in superoxide dismutase in
amyotrophic lateral sclerosis. Ann. Neurol. 41: 210-221, 1997.

24. Davidson, B. L.; Stein, C. S.; Heth, J. A.; Martins, I.; Kotin,
R. M.; Derksen, T. A.; Zabner, J.; Ghodsi, A.; Chiorini, J. A.: Recombinant
adeno-associated virus type 2, 4, and 5 vectors: transduction of variant
cell types and regions in the mammalian central nervous system. Proc.
Nat. Acad. Sci. 97: 3428-3432, 2000.

25. de Belleroche, J.; Orrell, R.; King, A.: Familial amyotrophic
lateral sclerosis/motor neurone disease (FALS): a review of current
developments. J. Med. Genet. 32: 841-847, 1995.

26. Deng, H.-X.; Hentati, A.; Tainer, J. A.; Iqbal, Z.; Cayabyab,
A.; Hung, W.-Y.; Getzoff, E. D.; Hu, P.; Herzfeldt, B.; Roos, R. P.;
Warner, C.; Deng, G.; Soriano, E.; Smyth, C.; Parge, H. E.; Ahmed,
A.; Roses, A. D.; Hallewell, R. A.; Pericak-Vance, M. A.; Siddique,
T.: Amyotrophic lateral sclerosis and structural defects in Cu,Zn
superoxide dismutase. Science 261: 1047-1051, 1993.

27. Dimos, J. T.; Rodolfa, K. T.; Niakan, K. K.; Weisenthal, L. M.;
Mitsumoto, H.; Chung, W.; Croft, G. F.; Saphier, G.; Leibel, R.; Goland,
R.; Wichterle, H.; Henderson, C. E.; Eggan, K.: Induced pluripotent
stem cells generated from patients with ALS can be differentiated
into motor neurons. Science 321: 1218-1221, 2008.

28. Drachman, D. B.; Frank, K.; Dykes-Hoberg, M.; Teismann, P.; Almer,
G.; Przedborski, S.; Rothstein, J. D.: Cyclooxygenase 2 inhibition
protects motor neurons and prolongs survival in a transgenic mouse
model of ALS. Ann. Neurol. 52: 771-778, 2002.

29. Dunckley, T.; Huentelman, M. J.; Craig, D. W.; Pearson, J. V.;
Szelinger, S.; Joshipura, K.; Halperin, R. F.; Stamper, C.; Jensen,
R.; Letizia, D.; Hesterlee, S. E.; Pestronk, A.; and 23 others:
Whole-genome analysis of amyotrophic lateral sclerosis. New Eng.
J. Med. 357: 775-788, 2007.

30. Engel, W. K.: Personal Communication. Bethesda, Md. 1976.

31. Engel, W. K.: Personal Communication. Bethesda, Md. 1976.

32. Engel, W. K.; Kurkland, L. L.; Klatzo, I.: An inherited disease
similar to amyotrophic lateral sclerosis with a pattern of posterior
column involvement. An intermediate form? Brain 82: 203-220, 1959.

33. Engel, W. K.; Kurland, L. T.; Klatzo, I.: An inherited disease
similar to amyotrophic lateral sclerosis with a pattern of posterior
column involvement: an intermediate form? Brain 82: 203-220, 1959.

34. Espinosa, R. E.; Okihiro, M. M.; Mulder, D. W.; Sayre, G. P.:
Hereditary amyotrophic lateral sclerosis: a clinical and pathologic
report with comments on classification. Neurology 12: 1-7, 1962.

35. Fang, F.; Kamel, F.; Lichtenstein, P.; Bellocco, R.; Sparen, P.;
Sandler, D. P.; Ye, W.: Familial aggregation of amyotrophic lateral
sclerosis. Ann. Neurol. 66: 94-99, 2009.

36. Feldmeyer, D.; Kask, K.; Brusa, R.; Kornau, H.-C.; Kolhekar, R.;
Rozov, A.; Burnashev, N.; Jensen, V.; Hvalby, O.; Sprengel, R.; Seeburg,
P. H.: Neurological dysfunctions in mice expressing different levels
of the Q/R site-unedited AMPAR subunit GluR-B. Nature Neurosci. 2:
57-64, 1999.

37. Fornai, F.; Longone, P.; Cafaro, L.; Kastsiuchenka, O.; Ferrucci,
M.; Manca, M. L.; Lazzeri, G.; Spalloni, A.; Bellio, N.; Lenzi, P.;
Modugno, N.; Siciliano, G.; Isidoro, C.; Murri, L.; Ruggieri, S.;
Paparelli, A.: Lithium delays progression of amyotrophic lateral
sclerosis. Proc. Nat. Acad. Sci. 105: 2052-2057, 2008. Note: Erratum:
Proc. Nat. Acad. Sci. 105: 16404 only, 2008.

38. Ganzini, L.; Johnston, W. S.; McFarland, B. H.; Tolle, S. W.;
Lee, M. A.: Attitudes of patients with amyotrophic lateral sclerosis
and their care givers toward assisted suicide. New Eng. J. Med. 339:
967-973, 1998.

39. Gardner, J. H.; Feldmahn, A.: Hereditary adult motor neuron disease. Trans.
Am. Neurol. Assoc. 91: 239-241, 1966.

40. Giess, R.; Holtmann, B.; Braga, M.; Grimm, T.; Muller-Myhsok,
B.; Toyka, K. V.; Sendtner, M.: Early onset of severe familial amyotrophic
lateral sclerosis with a SOD-1 mutation: potential impact of CNTF
as a candidate modifier gene. Am. J. Hum. Genet. 70: 1277-1286,
2002.

41. Gimenez-Roldan, S.; Esteban, A.: Prognosis in hereditary amyotrophic
lateral sclerosis. Arch. Neurol. 34: 706-708, 1977.

42. Green, J. B.: Familial amyotrophic lateral sclerosis occurring
in 4 generations. Neurology 10: 960-962, 1960.

43. Gros-Louis, F.; Lariviere, R.; Gowing, G.; Laurent, S.; Camu,
W.; Bouchard, J.-P.; Meininger, V.; Rouleau, G. A.; Julien, J.-P.
: A frameshift deletion in peripherin gene associated with amyotrophic
lateral sclerosis. J. Biol. Chem. 279: 45951-45956, 2004.

44. Gurney, M. E.; Pu, H.; Chiu, A. Y.; Dal Canto, M. C.; Polchow,
C. Y.; Alexander, D. D.; Caliendo, J.; Hentati, A.; Kwon, Y. W.; Deng,
H.-X.; Chen, W.; Zhai, P.; Sufit, R. L.; Siddique, T.: Motor neuron
degeneration in mice that express a human Cu,Zn superoxide dismutase
mutation. Science 264: 1772-1775, 1994. Note: Erratum: Science 269:
149 only, 1995.

45. Haberlandt, W. F.: Aspects genetiques de la sclerose laterale
amyotrophique. World Neurol. 2: 356-365, 1961.

46. Haberlandt, W. F.: Ergebnisse einer neurologisch-genetischen
Studie im nordwestdeutschen Raum.. (Abstract) Proc. 2nd Int. Cong.
Hum. Genet., Rome, Sept. 6-12, 1961 3: 1645-1651, 1963.

47. Hammond, W. A.: A Treatise on the Diseases of the Nervous System.
Philadelphia: Blakiston, Son & Co. (pub.) (7th ed.): 1888. Pp.
351 only.

48. He, C. Z.; Hays, A. P.: Expression of peripherin in ubiquinated
(sic) inclusions of amyotrophic lateral sclerosis. J. Neurol. Sci. 217:
47-54, 2004.

49. Hirano, A.; Kurland, L. T.; Sayre, G. P.: Familial amyotrophic
lateral sclerosis: a subgroup characterized by posterior and spinocerebellar
tract involvement and hyaline inclusions in the anterior horn cells. Arch.
Neurol. 16: 232-243, 1967.

50. Hirano, A.; Kurland, L. T.; Sayre, G. P.: Familial amyotrophic
lateral sclerosis: a subgroup characterized by posterior and spinocerebellar
tract involvement and hyaline inclusions in the anterior horn cells. Arch.
Neurol. 16: 232-243, 1967.

51. Horton, W. A.; Eldridge, R.; Brody, J. A.: Familial motor neuron
disease: evidence for at least three different types. Neurology 26:
460-465, 1976.

52. Hudson, A. J.: Amyotrophic lateral sclerosis and its association
with dementia, parkinsonism and other neurological disorders: a review. Brain 104:
217-247, 1981.

53. Husquinet, H.; Franck, G.: Hereditary amyotrophic lateral sclerosis
transmitted for five generations. Clin. Genet. 18: 109-115, 1980.

54. Iwasaki, Y.; Kinoshita, M.; Ikeda, K.: Concurrence of familial
amyotrophic lateral sclerosis with Ribbing's disease. Int. J. Neurosci. 58:
289-292, 1991.

55. Jones, C. T.; Brock, D. J. H.; Chancellor, A. M.; Warlow, C. P.;
Swingler, R. J.: Cu/Zn superoxide dismutase (SOD1) mutations and
sporadic amyotrophic lateral sclerosis. Lancet 342: 1050-1051, 1993.

56. Kaspar, B. K.; Llado, J.; Sherkat, N.; Rothstein, J. D.; Gage,
F. H.: Retrograde viral delivery of IGF-1 prolongs survival in a
mouse ALS model. Science 301: 839-842, 2003.

57. Kawahara, Y.; Ito, K.; Sun, H.; Aizawa, H.; Kanazawa, I.; Kwak,
S.: RNA editing and death of motor neurons: there is a glutamate-receptor
defect in patients with amyotrophic lateral sclerosis. (Letter) Nature 427:
801 only, 2004.

58. Kieran, D.; Woods, I.; Villunger, A.; Strasser, A.; Prehn, J.
H. M.: Deletion of the BH3-only protein puma protects motoneurons
from ER stress-induced apoptosis and delays motoneuron loss in ALS
mice. Proc. Nat. Acad. Sci. 104: 20606-20611, 2007.

59. King, A.; Houlden, H.; Hardy, J.; Lane, R.; Chancellor, A.; de
Belleroche, J.: Absence of linkage between chromosome 21 loci and
familial amyotrophic lateral sclerosis. J. Med. Genet. 30: 318,
1993.

60. Kudo, L. C.; Parfenova, L.; Vi, N.; Lau, K.; Pomakian, J.; Valdmanis,
P.; Rouleau, G. A.; Vinters, H. V.; Wiedau-Pazos, M.; Karsten, S.
L.: Integrative gene-tissue microarray-based approach for identification
of human disease biomarkers: application to amyotrophic lateral sclerosis. Hum.
Molec. Genet. 19: 3233-3253, 2010.

61. Kunst, C. B.: Complex genetics of amyotrophic lateral sclerosis. Am.
J. Hum. Genet. 75: 933-947, 2004.

62. Kurland, L. T.; Mulder, D. W.: Epidemiologic investigations of
amyotrophic lateral sclerosis. 2. Familial aggregations indicative
of dominant inheritance. Neurology 5: 182-196 and 249-268, 1955.

63. Lambrechts, D.; Poesen, K.; Fernandez-Santiago, R.; Al-Chalabi,
A.; Del Bo, R.; Van Vught, P. W. J.; Khan, S.; Marklund, S. L.; Brockington,
A.; van Marion, I.; Anneser, J.; Shaw, C.; and 12 others: Meta-analysis
of vascular endothelial growth factor variations in amyotrophic lateral
sclerosis: increased susceptibility in male carriers of the -2578AA
genotype. J. Med. Genet. 46: 840-846, 2009.

64. LaMonte, B. H.; Wallace, K. E.; Holloway, B. A.; Shelly, S. S.;
Ascano, J.; Tokito, M.; Van Winkle, T.; Howland, D. S.; Holzbaur,
E. L. F.: Disruption of dynein/dynactin inhibits axonal transport
in motor neurons causing late-onset progressive degeneration. Neuron 34:
715-727, 2002.

65. Landers, J. E.; Melki, J.; Meininger, V.; Glass, J. D.; van den
Berg, L. H.; van Es, M. A.; Sapp, P. C.; van Vught, P. W. J.; McKenna-Yasek,
D. M.; Blauw, H. M.; Cho, T.-J.; Polak, M.; and 34 others: Reduced
expression of the kinesin-associated protein 3 (KIFAP3) gene increases
survival in sporadic amyotrophic lateral sclerosis. Proc. Nat. Acad.
Sci. 106: 9004-9009, 2009.

66. Li, M.; Ona, V. O.; Guegan, C.; Chen, M.; Jackson-Lewis, V.; Andrews,
L. J.; Olszewski, A. J.; Stieg, P. E.; Lee, J.-P.; Przedborski, S.;
Friedlander, R. M.: Functional role of caspase-1 and caspase-3 in
an ALS transgenic mouse model. Science 288: 335-339, 2000.

67. Lincecum, J. M.; Vieira, F. G.; Wang, M. Z.; Thompson, K.; De
Zutter, G. S.; Kidd, J.; Moreno, A.; Sanchez, R.; Carrion, I. J.;
Levine, B. A.; Al-Nakhala, B. M.; Sullivan, S. M.; Gill, A.; Perrin,
S.: From transcriptome analysis to therapeutic anti-CD40L treatment
in the SOD1 model of amyotrophic lateral sclerosis. Nature Genet. 42:
392-399, 2010.

68. Liu, H.-N.; Sanelli, T.; Horne, P.; Pioro, E. P.; Strong, M. J.;
Rogaeva, E.; Bilbao, J.; Zinman, L.; Robertson, J.: Lack of evidence
of monomer/misfolded superoxide dismutase-1 in sporadic amyotrophic
lateral sclerosis. Ann. Neurol. 66: 75-80, 2009.

69. Liu, R.; Althaus, J. S.; Ellerbrock, B. R.; Becker, D. A.; Gurney,
M. E.: Enhanced oxygen radical production in a transgenic mouse model
of familial amyotrophic lateral sclerosis. Ann. Neurol. 44: 763-770,
1998.

70. Marden, J. J.; Harraz, M. M.; Williams, A. J.; Nelson, K.; Luo,
M.; Paulson, H.; Engelhardt, J. F.: Redox modifier genes in amyotrophic
lateral sclerosis in mice. J. Clin. Invest. 117: 2913-2919, 2007.

71. McKusick, V. A.: Osler as medical geneticist. Johns Hopkins
Med. J. 139: 163-174, 1976.

72. Meissner, F.; Molawi, K.; Zychlinsky, A.: Mutant superoxide dismutase
1-induced IL-1-beta accelerates ALS pathogenesis. Proc. Nat. Acad.
Sci. 107: 13046-13050, 2010.

73. Messer, A.; Plummer, J.; Maskin, P.; Coffin, J. M.; Frankel, W.
N.: Mapping of the motor neuron degeneration (Mnd) gene, a mouse
model of amyotrophic lateral sclerosis (ALS). Genomics 13: 797-802,
1992.

74. Millecamps, S.; Salachas, F.; Cazeneuve, C.; Gordon, P.; Bricka,
B.; Camuzat, A.; Guillot-Noel, L.; Russaouen, O.; Bruneteau, G.; Pradat,
P.-F.; Le Forestier, N.; Vandenberghe, N.; and 14 others: SOD1,
ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral
sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560,
2010.

75. Miller, T. M.; Kim, S. H.; Yamanaka, K.; Hester, M.; Umapathi,
P.; Arnson, H.; Rizo, L.; Mendell, J. R.; Gage, F. H.; Cleveland,
D. W.; Kaspar, B. K.: Gene transfer demonstrates that muscle is not
a primary target for non-cell-autonomous toxicity in familial amyotrophic
lateral sclerosis. Proc. Nat. Acad. Sci. 103: 19546-19551, 2006.

76. Mitchell, J.; Paul, P.; Chen, H.-J.; Morris, A.; Payling, M.;
Falchi, M.; Habgood, J.; Panoutsou, S.; Winkler, S.; Tisato, V.; Hajitou,
A.; Smith, B.; Vance, C.; Shaw, C.; Mazarakis, N. D.; de Belleroche,
J.: Familial amyotrophic lateral sclerosis is associated with a mutation
in D-amino acid oxidase. Proc. Nat. Acad. Sci. 107: 7556-7561, 2010.

77. Munch, C.; Sedlmeier, R.; Meyer, T.; Homberg, V.; Sperfeld, A.
D.; Kurt, A.; Prudlo, J.; Peraus, G.; Hanemann, C. O.; Stumm, G.;
Ludolph, A. C.: Point mutations of the p150 subunit of dynactin (DCTN1)
gene in ALS. Neurology 63: 724-726, 2004.

78. Myrianthopoulos, N. C.; Brown, I. A.: A genetic study of progressive
spinal muscular atrophy. Am. J. Hum. Genet. 6: 387-411, 1954.

79. Neumann, M.; Sampathu, D. M.; Kwong, L. K.; Truax, A. C.; Micsenyi,
M. C.; Chou, T. T.; Bruce, J.; Schuck, T.; Grossman, M.; Clark, C.
M.; McCluskey, L. F.; Miller, B. L.; Masliah, E.; Mackenzie, I. R.;
Feldman, H.; Feiden, W.; Kretzschmar, H. A.; Trojanowski, J. Q.; Lee,
V. M.-Y.: Ubiquitinated TDP-43 in frontotemporal lobar degeneration
and amyotrophic lateral sclerosis. Science 314: 130-133, 2006.

80. Nguyen, M. D.; Lariviere, R. C.; Julien, J.-P.: Deregulation
of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal
neurofilament inclusions. Neuron 30: 135-147, 2001.

81. Okado-Matsumoto, A.; Fridovich, I.: Amyotrophic lateral sclerosis:
a proposed mechanism. Proc. Nat. Acad. Sci. 99: 9010-9014, 2002.

82. Osler, W.: On heredity in progressive muscular atrophy as illustrated
in the Farr family of Vermont. Arch. Med. 4: 316-320, 1880.

83. Pedrini, S.; Sau, D.; Guareschi, S.; Bogush, M.; Brown, R. H.,
Jr.; Naniche, N.; Kia, A.; Trotti, D.; Pasinelli, P.: ALS-linked
mutant SOD1 damages mitochondria by promoting conformational changes
in Bcl-2. Hum. Molec. Genet. 19: 2974-2986, 2010.

84. Phillips, J.; Pyeritz, R.; Brooks, B.; Rosenthal, G.; Weintraub,
A.; Weinblatt, J.: Familial amyotrophic lateral sclerosis: an evaluation
of genetic counseling. (Abstract) Am. J. Hum. Genet. 30: 63A, 1978.

85. Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis
: Incidence of ALS in Italy: evidence for a uniform frequency in Western
countries. Neurology 56: 239-244, 2001.

86. Poser, C. M.; Johnson, M.; Bunch, L. D.: Familial amyotrophic
lateral sclerosis. Dis. Nerv. Syst. 26: 697-702, 1965.

87. Powers, J. M.; Horoupian, D. S.; Schaumburg, H. H.: Wetherbee
ail: documentation of a neurological disease in a Vermont family 90
years later. J. Canad. Sci. Neurol. 1: 139-140, 1974.

88. Pradat, P.-F.; Bruneteau, G.; Gonzalez de Aguilar, J.-L.; Dupuis,
L.; Jokic, N.; Salachas, F.; Le Forestier, N.; Echaniz-Laguna, A.;
Dubourg, O.; Hauw, J.-J.; Tranchant, C.; Loeffler, J.-P.; Meininger,
V.: Muscle Nogo-A expression is a prognostic marker in lower motor
neuron syndromes. Ann. Neurol. 62: 15-20, 2007.

89. Pramatarova, A.; Figlewicz, D. A.; Krizus, A.; Han, F. Y.; Ceballos-Picot,
I.; Nicole, A.; Dib, M.; Meininger, V.; Brown, R. H.; Rouleau, G.
A.: Identification of new mutations in the Cu/Zn superoxide dismutase
gene of patients with familial amyotrophic lateral sclerosis. Am.
J. Hum. Genet. 56: 592-596, 1995.

90. Rabin, S. J.; Mun, J.; Kim, H.; Baughn, M.; Libby, R. T.; Kim,
Y. J.; Fan, Y.; Libby, R. T.; La Spada, A.; Stone, B.; Ravits, J.
: Sporadic ALS has compartment-specific aberrant exon splicing and
altered cell-matrix adhesion biology. Hum. Molec. Genet. 19: 313-328,
2010.

91. Rakhit, R.; Robertson, J.; Vande Velde, C.; Horne, P.; Ruth,
D. M.; Griffin, J.; Cleveland, D. W.; Cashman, N. R.; Chakrabartty,
A.: An immunological epitope selective for pathological monomer-misfolded
SOD1 in ALS. Nature Med. 13: 754-759, 2007.

92. Raoul, C.; Buhler, E.; Sadeghi, C.; Jacquier, A.; Aebischer, P.;
Pettmann, B.; Henderson, C. E.; Haase, G.: Chronic activation in
presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback
loop involving Fas, Daxx, and FasL. Proc. Nat. Acad. Sci. 103: 6007-6012,
2006.

93. Raoul, C.; Estevez, A. G.; Nishimune, H.; Cleveland, D. W.; deLapeyriere,
O.; Henderson, C. E.; Hasse, G.; Pettmann, B.: Motoneuron death triggered
by a specific pathway downstream of Fas: potentiation by ALS-linked
SOD1 mutations. Neuron 35: 1067-1083, 2002.

94. Regal, L.; Vanopdenbosch, L.; Tilkin, P.; Van Den Bosch, L.; Thijs,
V.; Sciot, R.; Robberecht, W.: The G93C mutation in superoxide dismutase
1: clinicopathologic phenotype and prognosis. Arch. Neurol. 63:
262-267, 2006. Note: Erratum: Arch Neurol. 63: 963 only, 2006.

95. Ripps, M. E.; Huntley, G. W.; Hof, P. R.; Morrison, J. H.; Gordon,
J. W.: Transgenic mice expressing an altered murine superoxide dismutase
gene provide an animal model of amyotrophic lateral sclerosis. Proc.
Nat. Acad. Sci. 92: 689-693, 1995.

96. Rosen, D. R.; Siddique, T.; Patterson, D.; Figlewicz, D. A.; Sapp,
P.; Hentati, A.; Donaldson, D.; Goto, J.; O'Regan, J. P.; Deng, H.-X.;
Rahmani, Z.; Krizus, A.; and 21 others: Mutations in Cu/Zn superoxide
dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:
59-62, 1993. Note: Erratum: Nature: 364: 362 only, 1993.

97. Rothstein, J. D.; Martin, L. J.; Kuncl, R. W.: Decreased glutamate
transport by the brain and spinal cord in amyotrophic lateral sclerosis. New
Eng. J. Med. 326: 1464-1468, 1992.

98. Rowland, L. P.: Assisted suicide and alternatives in amyotrophic
lateral sclerosis. (Editorial) New Eng. J. Med. 339: 987-989, 1998.

99. Rowland, L. P.; Shneider, N. A.: Amyotrophic lateral sclerosis. New
Eng. J. Med. 344: 1688-1700, 2001.

100. Sabatelli, M.; Eusebi, F.; Al-Chalabi, A.; Conte, A.; Madia,
F.; Luigetti, M.; Mancuso, I.; Limatola, C.; Trettel, F.; Sobrero,
F.; Di Angelantonio, S.; Grassi, F.; and 11 others: Rare missense
variants of neuronal nicotinic acetylcholine receptor altering receptor
function are associated with sporadic amyotrophic lateral sclerosis. Hum.
Molec. Genet. 18: 3997-4006, 2009.

101. Sato, T.; Nakanishi, T.; Yamamoto, Y.; Andersen, P. M.; Ogawa,
Y.; Fukada, K.; Zhou, Z.; Aoike, F.; Sugai, F.; Nagano, S.; Hirata,
S.; Ogawa, M.; Nakano, R.; Ohi, T.; Kato, T.; Nakagawa, M.; Hamasaki,
T.; Shimizu, A.; Sakoda, S.: Rapid disease progression correlates
with instability of mutant SOD1 in familial ALS. Neurology 65: 1954-1957,
2005.

102. Scott-Emuakpor, A. B.; Heffelfinger, J.; Higgins, J. V.: A syndrome
of microcephaly and cataracts in four siblings: a new genetic syndrome? Am.
J. Dis. Child. 131: 167-169, 1977.

103. Shibata, N.; Hirano, A.; Kobayashi, M.; Sasaki, S.; Kato, T.;
Matsumoto, S.; Shiozawa, Z.; Komori, T.; Ikemoto, A.; Umahara, T.;
Asayama, K.: Cu/Zn superoxide dismutase-like immunoreactivity in
Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis. Neurosci.
Lett. 179: 149-152, 1994.

104. Siddique, T.: Personal Communication. Chicago, Ill. 11/17/1993.

105. Siddique, T.; Deng, H.-X.: Genetics of amyotrophic lateral sclerosis. Hum.
Molec. Genet. 5: 1465-1470, 1996.

106. Siddique, T.; Figlewicz, D. A.; Pericak-Vance, M. A.; Haines,
J. L.; Rouleau, G.; Jeffers, A. J.; Sapp, P.; Hung, W.-Y.; Bebout,
J.; McKenna-Yasek, D.; Deng, G.; Horvitz, H. R.; and 25 others:
Linkage of a gene causing familial amyotrophic lateral sclerosis to
chromosome 21 and evidence of genetic-locus heterogeneity. New Eng.
J. Med. 324: 1381-1384, 1991. Note: Erratum: New Eng. J. Med. 325:
71 only, 1991; Erratum: New Eng. J. Med. 325: 524 only, 1991.

107. Siddique, T.; Hong, S.-T.; Brooks, B. R.; Hung, W. Y.; Siddique,
N. A.; Rimmler, J.; Kaplan, J. P.; Haines, J. L.; Brown, R. H., Jr.;
Pericak-Vance, M. A.: X-linked dominant locus for late-onset familial
amyotrophic lateral sclerosis. Am. J. Hum. Genet. 63 (suppl.): A308
only, 1998.

108. Siddique, T.; Pericak-Vance, M. A.; Brooks, B. R.; Bias, W.;
Walker, N.; Siddique, N.; Hung, W.-Y.; Roses, A. D.: Linkage in familial
amyotrophic lateral sclerosis (ALS). (Abstract) Cytogenet. Cell Genet. 46:
692, 1987.

109. Siddique, T.; Pericak-Vance, M. A.; Brooks, B. R.; Roos, R. P.;
Tandan, R.; Nicholson, G.; Noore, F.; Antel, J. P.; Munsat, T. L.;
Phillips, K. L.; Hung, W.-Y.; Warner, K. L.; Bebout, J.; Bias, W.;
Roses, A. D.: Genetic linkage analysis in familial amyotrophic lateral
sclerosis. (Abstract) Cytogenet. Cell Genet. 51: 1080, 1989.

110. Siddique, T.; Pericak-Vance, M. A.; Caliendo, J.; Hong, S.-T.;
Hung, W.-Y.; Kaplan, J.; McKenna-Yasek, D.; Rimmler, J. B.; Sapp,
P.; Saunders, A. M.; Scott, W. K.; Siddique, N.; Haines, J. L.; Brown,
R. H.: Lack of association between apolipoprotein E genotype and
sporadic amyotrophic lateral sclerosis. Neurogenetics 1: 213-216,
1998.

111. Simpson, C. L.; Lemmens, R.; Miskiewicz, K.; Broom, W. J.; Hansen,
V. K.; van Vught, P. W. J.; Landers, J. E.; Sapp, P.; Van Den Bosch,
L.; Knight, J.; Neale, B. M.; Turner, M. R.; and 18 others: Variants
of elongator protein 3 (ELP3) gene are associated with motor neuron
degeneration. Hum. Molec. Genet. 18: 472-481, 2009.

112. Storkebaum, E.; Lambrechts, D.; Dewerchin, M.; Moreno-Murciano,
M.-P.; Appelmans, S.; Oh, H.; Van Damme, P.; Rutten, B.; Man, W.;
De Mol, M.; Wyns, S.; and 9 others: Treatment of motoneuron degeneration
by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature
Neurosci. 8: 85-92, 2005.

113. Swerts, L.; Van den Bergh, R.: Sclerose laterale amyotrophique
familiale: etude d'une famille atteinte sur trois generations. [Familial
amyotrophic lateral sclerosis: a study of a family suffering from
this disease for three generations]. J. Genet. Hum. 24: 247-255,
1976.

114. Tagerud, S.; Libelius, R.; Magnusson, C.: Muscle Nogo-A: a marker
for amyotrophic lateral sclerosis or for denervation? (Letter) Ann.
Neurol. 62: 676 only, 2007.

115. Takahashi, K.; Nakamura, H.; Okada, E.: Hereditary amyotrophic
lateral sclerosis: histochemical and electron microscopic study of
hyaline inclusions in motor neurons. Arch. Neurol. 27: 292-299,
1972.

116. Tateno, M.; Kato, S.; Sakurai, T.; Nukina, N.; Takahashi, R.;
Araki, T.: Mutant SOD1 impairs axonal transport of choline acetyltransferase
and acetylcholine release by sequestering KAP3. Hum. Molec. Genet. 18:
942-955, 2009.

117. Tateno, M.; Sadakata, H.; Tanaka, M.; Itohara, S.; Shin, R.-M.;
Miura, M.; Masuda, M.; Aosaki, T.; Urushitani, M.; Misawa, H.; Takahashi,
R.: Calcium-permeable AMPA receptors promote misfolding of mutant
SOD1 protein and development of amyotrophic lateral sclerosis in a
transgenic mouse model. Hum. Molec. Genet. 13: 2183-2196, 2004.

118. Thomson, A. F.; Alvarez, F. A.: Hereditary amyotrophic lateral
sclerosis. J. Neurol. Sci. 8: 101-110, 1969.

119. Tu, P.-H.; Raju, P.; Robinson, K. A.; Gurney, M. E.; Trojanowski,
J. Q.; Lee, V. M.-Y.: Transgenic mice carrying a human mutant superoxide
dismutase transgene develop neuronal cytoskeletal pathology resembling
human amyotrophic lateral sclerosis lesions. Proc. Nat. Acad. Sci. 93:
3155-3160, 1996.

120. Urushitani, M.; Ezzi, S. A.; Julien, J.-P.: Therapeutic effects
of immunization with mutant superoxide dismutase in mice models of
amyotrophic lateral sclerosis. Proc. Nat. Acad. Sci. 104: 2495-2500,
2007.

121. van Es, M. A.; Veldink, J. H.; Saris, C. G. J.; Blauw, H. M.;
van Vught, P. W. J.; Birve, A.; Lemmens, R.; Schelhaas, H. J.; Groen,
E. J. N.; Huisman, M. H. B.; van der Kooi, A. J.; de Visser, M.:
and 42 others: Genome-wide association study identifies 19p13.3
(UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic
lateral sclerosis. Nature Genet. 41: 1083-1087, 2009.

122. Veldink, J. H.; Kalmijn, S.; Van der Hout, A. H.; Lemmink, H.
H.; Groeneveld, G. J.; Lummen, C.; Scheffer, H.; Wokke, J. H. J.;
Van den Berg, L. H.: SMN genotypes producing less SMN protein increase
susceptibility to and severity of sporadic ALS. Neurology 65: 820-825,
2005.

123. Veltema, A. N.; Roos, R. A. C.; Bruyn, G. W.: Autosomal dominant
adult amyotrophic lateral sclerosis: a six generation Dutch family. J.
Neurol. Sci. 97: 93-115, 1990.

124. Wilkins, L. E.; Winter, R. M.; Myer, E. C.; Nance, W. E.: Dominantly
inherited amyotrophic lateral sclerosis (motor neuron disease). Med.
Coll. Va. Quart. 13(4): 182-186, 1977.

125. Williams, A. H. Valdez, G.; Moresi, V.; Qi, X.; McAnally, J.;
Elliott, J. L.; Bassel-Duby, R.; Sanes, J. R.; Olson, E. N.: MicroRNA-206
delays ALS progression and promotes regeneration of neuromuscular
synapses in mice. Science 326: 1549-1554, 2009.

126. Wills, A.-M.; Cronin, S.; Slowik, A.; Kasperaviciute, D.; Van
Es, M. A.; Morahan, J. M.; Valdmanis, P. N.; Meininger, V.; Melki,
J.; Shaw, C. E.; Rouleau, G. A.; Fisher, E. M. C.; and 11 others
: A large-scale international meta-analysis of paraoxonase gene polymorphisms
in sporadic ALS. Neurology 73: 16-24, 2009.

127. Wong, P. C.; Pardo, C. A.; Borchelt, D. R.; Lee, M. K.; Copeland,
N. G.; Jenkins, N. A.; Sisodia, S. S.; Cleveland, D. W.; Price, D.
L.: An adverse property of familial ALS-linked SOD1 mutation causes
motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:
1105-1116, 1995.

128. Wong, W.; Martin, L. J.: Skeletal muscle-restricted expression
of human SOD1 causes motor neuron degeneration in transgenic mice. Hum.
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 168605
*RECORD*
*FIELD* NO
168605
*FIELD* TI
#168605 PERRY SYNDROME
;;PARKINSONISM WITH ALVEOLAR HYPOVENTILATION AND MENTAL DEPRESSION
read more*FIELD* TX
A number sign (#) is used with this entry because Perry syndrome is
caused by mutations in the DCTN1 gene (601143).

CLINICAL FEATURES

Perry et al. (1975) described an unusual neuropsychiatric disorder
inherited in an autosomal dominant fashion through 3 generations of a
family. Symptoms began late in the fifth decade in 6 affected persons
and death occurred after 4 to 6 years. The earliest and most prominent
symptom was mental depression not responsive to antidepressant drugs or
electroconvulsive therapy. Sleep disturbances, exhaustion and marked
weight loss were features. Parkinsonism developed later, and respiratory
failure occurred terminally. Perry et al. (1975) found greatly
diminished taurine in plasma and cerebrospinal fluid, and at autopsy all
regions of the brain showed markedly reduced taurine content. Taurine is
a putative inhibitory synaptic transmitter.

Perry et al. (1990) described 2 additional affected persons in this
kindred. Neuropathologically, both showed severe neuronal loss and
reactive gliosis in the substantia nigra. Neurochemical studies showed a
marked depletion of dopamine in the substantia nigra, putamen, and
caudate nucleus, as well as reduction in serotonin content in the
substantia nigra. In both patients, glutamate contents were low in
frontal cortex and thalamus, and GABA contents were low in thalamus and
substantia nigra. In addition, phosphoethanolamine contents were reduced
in all brain regions of both patients, especially in the substantia
nigra. One patient with severe symptoms had low levels of homovanillic
acid, 5-hydroxyindoleacetic acid, and GABA in his CSF repeatedly for 3
years before death at age 58. The second patient died at the age of 51
of an unrelated cause before developing symptoms of the familial
disorder.

Between the times of the 2 reports by Perry et al. (1975, 1990), 2
additional unrelated families affected with the same disorder were
reported (Purdy et al., 1979; Roy et al., 1988). Brain content of
taurine was normal in the patients reported by Purdy et al. (1979). Both
Purdy et al. (1979) and Roy et al. (1988) emphasized alveolar
hypoventilation as a feature. Apathy and progressive weight loss were
also emphasized as early symptoms. Sudden death, presumably from failure
of central respiratory control, was a characteristic feature. Roy et al.
(1988) described a patient who after multiple episodes of respiratory
arrest was 'successfully managed with aggressive pulmonary care,
tracheostomy, and intermittent home mechanical ventilation, which,
combined with carbidopa/levodopa, allowed for a functional lifestyle
with improvement in apathy, mobility, and nutritional status.'

Lechevalier et al. (1992) described 5 cases in 1 family. Death caused by
central respiratory disorders occurred after 6 to 8 years of progressive
course. Autopsies in 2 cases were reported.

Tsuboi et al. (2002) reported a Japanese family in which 5 affected
members presented in the third and fourth decades with parkinsonism and
depression. Three affected members were studied in detail. Weight loss
and central hypoventilation developed in the later stages, leading to
death in at least 1 member. The disorder showed autosomal dominant
inheritance. Tsuboi et al. (2002) noted that hypoventilation is the most
critical feature of the disorder and suggested that altered
neurotransmitter levels may be causative.

MOLECULAR GENETICS

In affected members of 8 families with Perry syndrome, Farrer et al.
(2009) identified 5 different heterozygous mutations in the DCTN1 gene
(see, e.g., 601143.0006-601143.0007). In vitro functional expression
studies indicated that the mutations resulted in decreased microtubule
binding and intracytoplasmic inclusions.

*FIELD* RF
1. Farrer, M. J.; Hulihan, M. M.; Kachergus, J. M.; Dachsel, J. C.;
Stoessl, A. J.; Grantier, L. L.; Calne, S.; Calne, D. B.; Lechevalier,
B.; Chapon, F.; Tsuboi, Y.; Yamada, T.; and 10 others: DCTN1 mutations
in Perry syndrome. Nature Genet. 41: 163-165, 2009.

2. Lechevalier, B.; Schupp, C.; Fallet-Bianco, C.; Viader, F.; Eustache,
F.; Chapon, F.; Morin, P.: Syndrome Parkinsonien familial avec athymhormie
et hypoventilation. Rev. Neurol. 148: 39-46, 1992.

3. Perry, T. L.; Bratty, P. J. A.; Hansen, S.; Kennedy, J.; Urquhart,
N.; Dolman, C. L.: Hereditary mental depression and parkinsonism
with taurine deficiency. Arch. Neurol. 32: 108-113, 1975.

4. Perry, T. L.; Wright, J. M.; Berry, K.; Hansen, S.; Perry, T. L.,
Jr.: Dominantly inherited apathy, central hypoventilation, and parkinson's
syndrome: clinical, biochemical, and neuropathologic studies of 2
new cases. Neurology 40: 1882-1887, 1990.

5. Purdy, A.; Hahn, A.; Barnett, H. J. M.; Bratty, P.; Ahmad, D.;
Lloyd, K. G.; McGeer, E. G.; Perry, T. L.: Familial fatal parkinsonism
with alveolar hypoventilation and mental depression. Ann. Neurol. 6:
523-531, 1979.

6. Roy, E. P., III; Riggs, J. E.; Martin, J. D.; Ringel, R. A.; Gutmann,
L.: Familial parkinsonism, apathy, weight loss, and central hypoventilation:
successful long-term management. Neurology 38: 637-639, 1988.

7. Tsuboi, Y.; Wszolek, Z. K.; Kusuhara, T.; Doh-ura, K.; Yamada,
T.: Japanese family with parkinsonism, depression, weight loss, and
central hypoventilation. Neurology 58: 1025-1030, 2002.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Weight];
Weight loss

RESPIRATORY:
Hypoventilation, central;
Respiratory insufficiency

NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Insomnia;
Neuronal loss in the substantia nigra;
[Behavioral/psychiatric manifestations];
Depression;
Apathy;
Social withdrawal

MISCELLANEOUS:
Onset in fourth to fifth decade;
Rapid progression;
Central hypoventilation occurs late in the disease and is often fatal

MOLECULAR BASIS:
Caused by mutation in the dynactin 1 gene (DCTN1, 601143.0006).

*FIELD* CN
Cassandra L. Kniffin - revised: 02/10/2009

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

*FIELD* ED
ckniffin: 02/10/2009

*FIELD* CN
Cassandra L. Kniffin - updated: 2/10/2009
Cassandra L. Kniffin - updated: 6/3/2002

*FIELD* CD
Victor A. McKusick: 1/23/1991

*FIELD* ED
ckniffin: 12/09/2009
wwang: 2/24/2009
ckniffin: 2/10/2009
alopez: 3/17/2004
carol: 6/3/2002
ckniffin: 6/3/2002
mimadm: 1/14/1995
carol: 6/4/1992
supermim: 3/16/1992
carol: 2/21/1991
carol: 1/23/1991

MIM 601143
*RECORD*
*FIELD* NO
601143
*FIELD* TI
*601143 DYNACTIN 1; DCTN1
;;p150(GLUED), DROSOPHILA, HOMOLOG OF
*FIELD* TX

DESCRIPTION
read more
Cytoplasmic dynein is a microtubule-based biologic motor protein.
Holzbaur and Tokito (1996) noted that dyneins were initially discovered
as enzymes that couple ATP hydrolysis to provide a force for cellular
motility in eukaryotic cilia and flagella. A distinct cytoplasmic form
of dynein (600112) was subsequently characterized and thought to be
responsible for the intracellular retrograde motility of vesicles and
organelles along microtubules (Holzbaur and Vallee, 1994). A large
macromolecular complex, dynactin, is required for the cytoplasmic
dynein-driven movement of organelles along microtubules. Dynactin is
composed of 10 distinct polypeptides of 150, 135, 62, 50 (DCTN2;
607376), 45, 42, 37, 32, 27, and 24 kD, with a combined mass of 10
million daltons. The largest polypeptide of the dynactin complex,
p150(Glued), binds directly to microtubules and to cytoplasmic dynein.
The binding of dynactin to dynein is critical for neuronal function, as
antibodies that specifically disrupt this binding block vesicle motility
along microtubules in extruded squid axoplasm. Holzbaur and Tokito
(1996) stated that the dynein-dynactin interaction is probably a key
component of the mechanism of axonal transport of vesicles and
organelles. Further evidence for a critical role for dynactin in vivo
comes from the analysis of mutations in the homologous gene in
Drosophila. Mutant alleles of the 'glued' gene induced disruption of the
neurons of the optic lobe and compound eye in heterozygotes; null
mutations are lethal.

CLONING

Holzbaur and Tokito (1996) isolated and characterized cDNA clones
encoding human p150(Glued), as well as alternatively spliced isoforms.
Using these to isolate genomic clones, they found by genomic Southern
blots that there is a single gene in the human, as had previously been
observed in rat and chick.

Jang et al. (1997) cloned and characterized mouse Dctn1. The mouse
protein shares 95% amino acid identity with the human protein. The
authors found no abnormalities of the gene in mnd2 mice.

GENE FUNCTION

Eaton et al. (2002) disrupted the dynactin complex in Drosophila, using
3 separate perturbations: dsRNA interference with arp1 (homolog of
ACTR1A; 605143), mutation in p150/Glued, and a dominant-negative Glued
transgene. In all 3 cases, the disruption resulted in an increase in the
frequency and extent of synaptic retraction events at the neuromuscular
junction. Eaton et al. (2002) concluded that dynactin functions locally
within the presynaptic arbor to promote synapse stability at the
neuromuscular junction.

Kim et al. (2004) showed that BBS4 (600374) protein localizes to the
centriolar satellites of centrosomes and basal bodies of primary cilia,
where it functions as an adaptor of the p150(glued) subunit of the
dynein transport machinery to recruit pericentriolar material-1 protein
(PCM1; 600299) and its associated cargo to the satellites. Silencing of
BBS4 induces PCM1 mislocalization and concomitant deanchoring of
centrosomal microtubules, arrest in cell division, and apoptotic cell
death.

Gauthier et al. (2004) showed that huntingtin (613004) specifically
enhances vesicular transport of brain-derived neurotrophic factor (BDNF;
113505) along microtubules. They determined that huntingtin-mediated
transport involves huntingtin-associated protein-1 (HAP1; 600947) and
the p150(Glued) subunit of dynactin, an essential component of molecular
motors. BDNF transport was attenuated both in the disease context and by
reducing the levels of wildtype huntingtin. The alteration of the
huntingtin/HAP1/p150(Glued) complex correlated with reduced association
of motor proteins with microtubules. The
polyglutamine-huntingtin-induced transport deficit resulted in the loss
of neurotrophic support and neuronal toxicity. Gauthier et al. (2004)
concluded that a key role of huntingtin is to promote BDNF transport and
suggested that loss of this function might contribute to pathogenesis.

Using in vivo skin-specific lentiviral RNA interference, Williams et al.
(2011) investigated spindle orientation regulation and provided direct
evidence that LGN (609245), NuMA (164009), and dynactin are involved. In
compromising asymmetric cell divisions, Williams et al. (2011) uncovered
profound defects in stratification, differentiation, and barrier
formation, and implicated Notch (190198) signaling as an important
effector. Williams et al. (2011) concluded that asymmetric cell division
components act by reorientating mitotic spindles to achieve
perpendicular divisions, which in turn promote stratification and
differentiation. Furthermore, the resemblance between their knockdown
phenotypes and Rbpj (147183) loss-of-function mutants provided important
clues that suprabasal Notch signaling is impaired when asymmetric cell
divisions do not occur.

GENE STRUCTURE

Collin et al. (1998) found that the DCTN1 gene spans approximately 19.4
kb of genomic DNA and consists of at least 32 exons ranging in size from
15 to 499 bp.

Pushkin et al. (2001) showed by Southern blot and BAC analyses that the
DCTN1 and SLC4A5 (606757) proteins are encoded by a single locus. The
DCTN1-SLC4A5 locus spans approximately 230 kb and contains 66 exons.
Approximately 200 kb encode SLC4A5. DCTN1 is encoded by exons 1 through
alternative exon 32. The same locus therefore uniquely encodes both a
membrane protein (SLC4A5) and a cytoplasmic protein (DCTN1) with
distinct functions.

MAPPING

By fluorescence in situ hybridization, Holzbaur and Tokito (1996) mapped
the DCTN1 gene to 2p13. They noted that the location of the gene
corresponds to that of a form of recessive limb-girdle muscular
dystrophy (see LGMD2B; 253601). Also, this region of human chromosome 2
shows syntenic homology with a region of mouse chromosome 6 containing
the mnd2 mouse mutation, which exhibits symptoms resembling human motor
neuron disease.

Korthaus et al. (1997) presented evidence that the DCTN1 gene maps to
chromosome 2 between TGFA and D2S1394.

MOLECULAR GENETICS

Puls et al. (2003) identified a gly59-to-ser mutation (601143.0001) in
the DCTN1 gene in a family with slowly progressive autosomal dominant
distal hereditary motor neuronopathy with vocal paresis (HMN7B; 607641).

Among 250 patients with a putative diagnosis of amyotrophic lateral
sclerosis (ALS; 105400), Munch et al. (2004) identified 3 mutations in
the DCTN1 gene (601143.0002-601143.0004) in 3 families. The authors
distinguished the phenotype in their patients from that reported by Puls
et al. (2003) by the presence of upper motor neuron signs, although
specific clinical details were lacking. Munch et al. (2004) suggested
that mutations in the DCTN1 gene may be a susceptibility factor for ALS.

In affected members of 8 families with Perry syndrome (168605), Farrer
et al. (2009) identified 5 different heterozygous mutations in the DCTN1
gene (see, e.g., 601143.0006-601143.0007). In vitro functional
expression studies indicated that the mutations resulted in decreased
microtubule binding and intracytoplasmic inclusions.

Vilarino-Guell et al. (2009) sequenced the DCTN1 gene in 286 individuals
with Parkinson disease (PD; 168600), frontotemporal lobar degeneration
(FTLD; 600274), or ALS. None of the 36 variants identified segregated
conclusively within families, suggesting that DCTN1 mutations are rare
and do not play a common role in these diseases. Further analysis of 440
patients with PD, 374 with FTLD, and 372 with ALS without a family
history also failed to find an association between DCTN1 variants and
disease. In fact, the previously reported pathogenic mutation T1249I
(601143.0002) was identified in 3 of 435 controls and did not segregate
in a large pedigree with Parkinson disease, thus weakening the evidence
for the pathogenicity of this variant.

*FIELD* AV
.0001
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VIIB
DCTN1, GLY59SER

In a North American family with a slowly progressive, autosomal dominant
form of lower motor neuron with vocal cord paresis but without sensory
symptoms (607641), Puls et al. (2003) found a single-basepair change in
the DCTN1 gene (957C-T) resulting in an amino acid substitution of
serine for glycine at position 59 in affected family members. The G59S
substitution occurred in the highly conserved CAP-Gly motif of the
p150(Glued) subunit of dynactin, a domain that binds directly to
microtubules. The transport protein dynactin is required for
dynein-mediated retrograde transport of vesicles and organelles along
microtubules. Overexpression of dynamitin (607376), the p50 subunit of
the dynactin complex, disrupts the complex and produces a late-onset,
progressive motor neuron disease in transgenic mice (LaMonte et al.,
2002).

Based on crystal structure, gly59 is embedded in a beta-sheet. In
budding yeast, Moore et al. (2009) generated a G59S-analogous mutation
that resulted in complete loss of the CAP-Gly domain. Functional
expression studies showed that the CAP-Gly domain has a critical role in
the initiation and persistence of dynein-dependent movement of the
mitotic spindle and nucleus, but was otherwise dispensable for
dynein-based movement. The function also appeared to be
context-dependent, such as during mitosis, indicating that CAP-Gly
activity may only be necessary when dynein needs to overcome high force
thresholds to produce movement. The CAP-Gly domain was not the primary
link between dynactin and microtubules, although it was involved in the
interaction.

.0002
AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO
DCTN1, THR1249ILE

In a woman with a disorder similar to amyotrophic lateral sclerosis
(105400), Munch et al. (2004) identified a heterozygous 4546C-T
transition in exon 13 of the DCTN1 gene, resulting in a thr1249-to-ile
(T1249I) substitution. She had disease onset at age 56 years, with gait
disturbance and distal lower limb muscle weakness and atrophy. The
symptoms were slowly progressive over 4 years. There was no involvement
of the upper limbs or bulbar region. There was no family history. The
mutation was not identified in 150 control subjects. See also 607641.

Vilarino-Guell et al. (2009) identified the T1249I variant in 3 of 435
controls, 5 of 440 patients with Parkinson disease (168600), 1 of 374
with frontotemporal lobar degeneration (600274), and 5 of 372 patients
with ALS. Lack of segregation of the variant in a large pedigree with
Parkinson disease weakened the evidence for the pathogenicity of this
variant.

.0003
AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO
DCTN1, MET571THR

In a woman with probable ALS (105400), Munch et al. (2004) identified a
heterozygous 2512T-C transition in exon 15 of the DCTN1 gene, resulting
in a met571-to-thr (M571T) substitution. She had onset of upper limb
involvement at age 48 years and developed bulbar symptoms within 8
years. Her sister was similarly affected, although DNA was not
available. The mutation was not identified in 150 control subjects.

.0004
AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO
DCTN1, ARG785TRP

In 2 brothers with probable ALS (105400), Munch et al. (2004) identified
a heterozygous 3153C-T transition in exon 20 of the DCTN1 gene,
resulting in an arg785-to-trp (R785W) substitution. The proband had
upper limb onset at age 55 years, whereas his brother had bulbar onset
at age 64 years. The asymptomatic mother and sister carried the same
mutation, suggesting incomplete penetrance. The mutation was not
identified in 150 control subjects.

.0005
AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO
DCTN1, ARG1101LYS

In a patient with amyotrophic lateral sclerosis (105400), Munch et al.
(2005) identified a heterozygous 4102G-A transition in the DCTN1 gene,
resulting in an arg1101-to-lys (R1101K) substitution. The patient's
brother, who also carried the R1101K mutation, had frontotemporal
dementia without motor involvement. Family history revealed that 2
additional family members reportedly had motor neuron disease and
frontotemporal dementia, respectively, but their DNA was not available
for testing. The mutation was not identified in 500 control individuals.
Despite the molecular findings, Munch et al. (2005) suggested that the
R1101K variant may not be the primary gene defect in this family.

.0006
PERRY SYNDROME
DCTN1, GLY71ARG

In affected members of 2 unrelated families with Perry syndrome
(168605), Farrer et al. (2009) identified a heterozygous 211G-A
transition in exon 2 of the DCTN1 gene, resulting in a gly71-to-arg
(G71R) substitution in a highly conserved residue within the GKNDG
binding motif of the CAP-Gly domain. The families were of Canadian and
Turkish ancestry, respectively, and haplotype analysis excluded a
founder effect. In vitro functional expression studies showed that the
mutation decreased microtubule binding and resulted in intracytoplasmic
inclusions.

.0007
PERRY SYNDROME
DCTN1, GLN74PRO

In affected members of a Japanese family with Perry syndrome (168605),
Farrer et al. (2009) identified a heterozygous 221A-C transversion in
exon 2 of the DCTN1 gene, resulting in a gln74-to-pro (Q74P)
substitution in a highly conserved residue adjacent to the GKNDG binding
motif of the CAP-Gly domain. In vitro functional expression studies
showed that the mutation decreased microtubule binding and resulted in
intracytoplasmic inclusions.

*FIELD* RF
1. Collin, G. B.; Nishina, P. M.; Marshall, J. D.; Naggert, J. K.
: Human DCTN1: genomic structure and evaluation as a candidate for
Alstrom syndrome. Genomics 53: 359-364, 1998.

2. Eaton, B. A.; Fetter, R. D.; Davis, G. W.: Dynactin is necessary
for synapse stabilization. Neuron 34: 729-741, 2002.

3. Farrer, M. J.; Hulihan, M. M.; Kachergus, J. M.; Dachsel, J. C.;
Stoessl, A. J.; Grantier, L. L.; Calne, S.; Calne, D. B.; Lechevalier,
B.; Chapon, F.; Tsuboi, Y.; Yamada, T.; and 10 others: DCTN1 mutations
in Perry syndrome. Nature Genet. 41: 163-165, 2009.

4. Gauthier, L. R.; Charrin, B. C.; Borrell-Pages, M.; Dompierre,
J. P.; Rangone, H.; Cordelieres, F. P.; De Mey, J.; MacDonald, M.
E.; Lebmann, V.; Humbert, S.; Saudou, F.: Huntingtin controls neurotrophic
support and survival of neurons by enhancing BDNF vesicular transport
along microtubules. Cell 118: 127-138, 2004.

5. Holzbaur, E. L. F.; Tokito, M. K.: Localization of the DCTN1 gene
encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ
hybridization. Genomics 31: 398-399, 1996.

6. Holzbaur, E. L. F.; Vallee, R. B.: Dyneins: molecular structure
and cellular function. Ann. Rev. Cell Biol. 10: 339-372, 1994.

7. Jang, W.; Weber, J. S.; Tokito, M. K.; Holzbaur, E. L. F.; Meisler,
M. H.: Mouse p150(Glued) (dynactin 1) cDNA sequence and evaluation
as a candidate for the neuromuscular disease mutation mnd2. Biochem.
Biophys. Res. Commun. 231: 344-347, 1997.

8. Kim, J. C.; Badano, J. L.; Sibold, S.; Esmail, M. A.; Hill, J.;
Hoskins, B. E.; Leitch, C. C.; Venner, K.; Ansley, S. J.; Ross, A.
J.; Leroux, M. R.; Katsanis, N.; Beales, P. L.: The Bardet-Biedl
protein BBS4 targets cargo to the pericentriolar region and is required
for microtubule anchoring and cell cycle progression. Nature Genet. 36:
462-470, 2004.

9. Korthaus, D.; Wedemeyer, N.; Lengeling, A.; Ronsiek, M.; Jockusch,
H.; Schmitt-John, T.: Integrated radiation hybrid map of human chromosome
2p13: possible involvement of dynactin in neuromuscular diseases. Genomics 43:
242-244, 1997.

10. LaMonte, B. H.; Wallace, K. E.; Holloway, B. A.; Shelly, S. S.;
Ascano, J.; Tokito, M.; Van Winkle, T.; Howland, D. S.; Holzbaur,
E. L. F.: Disruption of dynein/dynactin inhibits axonal transport
in motor neurons causing late-onset progressive degeneration. Neuron 34:
715-727, 2002.

11. Moore, J. K.; Sept, D.; Cooper, J. A.: Neurodegeneration mutations
in dynactin impair dynein-dependent nuclear migration. Proc. Nat.
Acad. Sci. 106: 5147-5152, 2009.

12. Munch, C.; Rosenbohm, A.; Sperfeld, A.-D.; Uttner, I.; Reske,
S.; Krause, B. J.; Sedlmeier, R.; Meyer, T.; Hanemann, C. O.; Stumm,
G.; Ludolph, A. C.: Heterozygous R1101K mutation of the DCTN1 gene
in a family with ALS and FTD. Ann. Neurol. 58: 777-780, 2005.

13. Munch, C.; Sedlmeier, R.; Meyer, T.; Homberg, V.; Sperfeld, A.
D.; Kurt, A.; Prudlo, J.; Peraus, G.; Hanemann, C. O.; Stumm, G.;
Ludolph, A. C.: Point mutations of the p150 subunit of dynactin (DCTN1)
gene in ALS. Neurology 63: 724-726, 2004.

14. Puls, I.; Jonnakuty, C.; LaMonte, B. H.; Holzbaur, E. L. F.; Tokito,
M.; Mann, E.; Floeter, M. K.; Bidus, K.; Drayna, D.; Oh, S. J.; Brown,
R. H., Jr.; Ludlow, C. L.; Fischbeck, K. H.: Mutant dynactin in motor
neuron disease. Nature Genet. 33: 455-456, 2003.

15. Pushkin, A.; Abuladze, N.; Newman, D.; Tatishchev, S.; Kurtz,
I.: Genomic organization of the DCTN1-SLC4A5 locus encoding both
NBC4 and p150(Glued). Cytogenet. Cell Genet. 95: 163-168, 2001.

16. Vilarino-Guell, C.; Wider, C.; Soto-Ortolaza, A. I.; Cobb, S.
A.; Kachergus, J. M.; Keeling, B. H.; Dachsel, J. C.; Hulihan, M.
M.; Dickson, D. W.; Wszolek, Z. K.; Uitti, R. J.; Graff-Radford, N.
R.; and 14 others: Characterization of DCTN1 genetic variability
in neurodegeneration. Neurology 72: 2024-2028, 2009.

17. Williams, S. E.; Beronja, S.; Pasolli, H. A.; Fuchs, E.: Asymmetric
cell divisions promote Notch-dependent epidermal differentiation. Nature 470:
353-358, 2011.

*FIELD* CN
Ada Hamosh - updated: 6/29/2011
Cassandra L. Kniffin - updated: 12/15/2009
Cassandra L. Kniffin - updated: 10/14/2009
Cassandra L. Kniffin - updated: 2/10/2009
Cassandra L. Kniffin - updated: 3/6/2006
Cassandra L. Kniffin - updated: 3/4/2005
Stylianos E. Antonarakis - updated: 8/3/2004
Victor A. McKusick - updated: 4/27/2004
Victor A. McKusick - updated: 3/19/2003
Dawn Watkins-Chow - updated: 11/27/2002
Paul J. Converse - updated: 6/24/2002
Carol A. Bocchini - updated: 2/24/1999
Victor A. McKusick - updated: 9/4/1997

*FIELD* CD
Victor A. McKusick: 3/20/1996

*FIELD* ED
carol: 09/21/2012
alopez: 7/5/2011
terry: 6/29/2011
carol: 12/23/2009
ckniffin: 12/15/2009
wwang: 10/23/2009
ckniffin: 10/14/2009
carol: 9/15/2009
wwang: 2/24/2009
ckniffin: 2/10/2009
ckniffin: 3/16/2007
wwang: 3/10/2006
ckniffin: 3/6/2006
ckniffin: 4/4/2005
wwang: 3/17/2005
wwang: 3/16/2005
wwang: 3/11/2005
ckniffin: 3/4/2005
mgross: 8/3/2004
alopez: 5/3/2004
alopez: 4/27/2004
alopez: 4/2/2003
alopez: 3/20/2003
terry: 3/19/2003
carol: 12/6/2002
tkritzer: 11/27/2002
mgross: 11/22/2002
mgross: 6/24/2002
alopez: 5/11/2001
terry: 2/25/1999
carol: 2/24/1999
terry: 9/10/1997
terry: 9/4/1997
mark: 3/21/1996

MIM 607641
*RECORD*
*FIELD* NO
607641
*FIELD* TI
#607641 NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VIIB; HMN7B
;;HMN VIIB;;
NEUROPATHY, DISTAL HEREDITARY MOTOR, TYPE VIIB;;
read moreDHMN7B;;
NEUROPATHY, DISTAL HEREDITARY MOTOR, WITH VOCAL CORD PARALYSIS, TYPE
VIIB;;
LOWER MOTOR NEURON DISEASE, DYNACTIN TYPE
*FIELD* TX
A number sign (#) is used with this entry because distal hereditary
motor neuronopathy type VIIB (dHMN7B or HMN7B) is caused by heterozygous
mutation in the dynactin-1 gene (601143) on chromosome 2p13.

See also HMN7A (158580), which is caused by mutation in the SLC5A7 gene
(608761) on chromosome 2q14.

For a general phenotypic description and a discussion of genetic
heterogeneity of distal HMN, see HMN type I (HMN1; 182960).

CLINICAL FEATURES

Puls et al. (2003) identified a family with a slowly progressive,
autosomal dominant form of motor neuron disease without sensory
symptoms. Onset of the disorder was in early adulthood with breathing
difficulty due to vocal fold paralysis, progressive facial weakness, and
weakness and muscle atrophy in the hands. Weakness and muscle atrophy in
the distal lower extremities developed later.

There is some phenotypic overlap between this disorder and amyotrophic
lateral sclerosis (ALS; 105400).

MAPPING

Puls et al. (2003) performed a genomewide screen in their family with
lower motor neuron disease and demonstrated linkage to 2p13 with a
maximum lod score of 4.05 at D2S2109 at recombination fraction theta =
0.0. Multipoint linkage analysis gave a maximum lod score of 5.6.

MOLECULAR GENETICS

Puls et al. (2003) found a gly59-to-ser mutation in the DCTN1 gene
(G59S; 601143.0001) in all affected individuals of the family they
studied with lower motor neuron disease.

Among 250 patients with a putative diagnosis of amyotrophic lateral
sclerosis, Munch et al. (2004) identified a woman with a mutation in the
DCTN1 gene (T1249I; 601143.0002). She had onset at age 56 years of
distal lower limb weakness and atrophy without involvement of the upper
limbs or bulbar muscles. Munch et al. (2004) considered the phenotype in
this patient to be different from that reported by Puls et al. (2003);
they stated that 'one of the main differences' was 'the lack of upper
motor neuron signs in patients with the G59S mutation,' but specific
clinical details were lacking.

*FIELD* RF
1. Munch, C.; Sedlmeier, R.; Meyer, T.; Homberg, V.; Sperfeld, A.
D.; Kurt, A.; Prudlo, J.; Peraus, G.; Hanemann, C. O.; Stumm, G.;
Ludolph, A. C.: Point mutations of the p150 subunit of dynactin (DCTN1)
gene in ALS. Neurology 63: 724-726, 2004.

2. Puls, I.; Jonnakuty, C.; LaMonte, B. H.; Holzbaur, E. L. F.; Tokito,
M.; Mann, E.; Floeter, M. K.; Bidus, K.; Drayna, D.; Oh, S. J.; Brown,
R. H., Jr.; Ludlow, C. L.; Fischbeck, K. H.: Mutant dynactin in motor
neuron disease. Nature Genet. 33: 455-456, 2003.

*FIELD* CS
INHERITANCE:
Autosomal dominant

RESPIRATORY:
[Larynx];
Breathing difficulty due to vocal cord paralysis

NEUROLOGIC:
[Central nervous system];
Lower motor neuron disease;
Facial weakness;
Hand muscle weakness;
Hand muscle atrophy;
Breathing difficulty due to vocal cord paralysis;
Lower limb muscle weakness (occurs later);
Lower limb muscle atrophy;
No sensory symptoms

MISCELLANEOUS:
Onset in early adulthood;
Slowly progressive

MOLECULAR BASIS:
Caused by mutation in the dynactin-1 gene (DCTN1, 601143.0001)

*FIELD* CD
Cassandra L. Kniffin: 12/10/2003

*FIELD* ED
ckniffin: 12/10/2003
alopez: 3/20/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 3/4/2005

*FIELD* CD
Victor A. McKusick: 3/20/2003

*FIELD* ED
carol: 03/14/2013
ckniffin: 4/23/2010
carol: 3/16/2007
ckniffin: 3/16/2007
ckniffin: 4/4/2005
wwang: 3/16/2005
carol: 3/15/2005
ckniffin: 3/15/2005
ckniffin: 3/4/2005
alopez: 4/10/2003
alopez: 4/2/2003
alopez: 3/20/2003