RBCC Red Blood Cell Collection

TARDBP (TDP43) [Confidence: low (only semi-automatic identification from reviews)]
TAR DNA-binding protein 43; TDP-43
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q13148
ID TADBP_HUMAN Reviewed; 414 AA.
AC Q13148; A4GUK4; A4GUK5; A4GUK6; B2R629; E2PU12; Q53H27; Q6FI92;
read moreAC Q96DJ0;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=TAR DNA-binding protein 43;
DE Short=TDP-43;
GN Name=TARDBP; Synonyms=TDP43;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND CHARACTERIZATION.
RC TISSUE=Cervix carcinoma;
RX PubMed=7745706;
RA Ou S.-H.I., Wu F., Harrich D., Garcia-Martinez L.F., Gaynor R.B.;
RT "Cloning and characterization of a novel cellular protein, TDP-43,
RT that binds to human immunodeficiency virus type 1 TAR DNA sequence
RT motifs.";
RL J. Virol. 69:3584-3596(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND
RP UBIQUITINATION.
RX PubMed=17481916; DOI=10.1016/j.mcn.2007.03.007;
RA Strong M.J., Volkening K., Hammond R., Yang W., Strong W.,
RA Leystra-Lantz C., Shoesmith C.;
RT "TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-
RT binding protein.";
RL Mol. Cell. Neurosci. 35:320-327(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [8]
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph, and Testis;
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 [10]
RP PROTEIN SEQUENCE OF 122-136 AND 276-293, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Afjehi-Sadat L.;
RL Submitted (MAR-2007) to UniProtKB.
RN [11]
RP PROTEIN SEQUENCE OF 252-263; 276-293 AND 409-414, SUBCELLULAR
RP LOCATION, PHOSPHORYLATION, AND UBIQUITINATION.
RX PubMed=17023659; DOI=10.1126/science.1134108;
RA Neumann M., Sampathu D.M., Kwong L.K., Truax A.C., Micsenyi M.C.,
RA Chou T.T., Bruce J., Schuck T., Grossman M., Clark C.M.,
RA McCluskey L.F., Miller B.L., Masliah E., Mackenzie I.R., Feldman H.,
RA Feiden W., Kretzschmar H.A., Trojanowski J.Q., Lee V.M.-Y.;
RT "Ubiquitinated TDP-43 in frontotemporal lobar degeneration and
RT amyotrophic lateral sclerosis.";
RL Science 314:130-133(2006).
RN [12]
RP FUNCTION.
RX PubMed=11285240; DOI=10.1093/emboj/20.7.1774;
RA Buratti E., Doerk T., Zuccato E., Pagani F., Romano M., Baralle F.E.;
RT "Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo
RT CFTR exon 9 skipping.";
RL EMBO J. 20:1774-1784(2001).
RN [13]
RP RNA-BINDING, AND MUTAGENESIS.
RX PubMed=11470789; DOI=10.1074/jbc.M104236200;
RA Buratti E., Baralle F.E.;
RT "Characterization and functional implications of the RNA binding
RT properties of nuclear factor TDP-43, a novel splicing regulator of
RT CFTR exon 9.";
RL J. Biol. Chem. 276:36337-36343(2001).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292, 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 ATNX2, AND CHARACTERIZATION OF VARIANT ALS10 LYS-331.
RX PubMed=20740007; DOI=10.1038/nature09320;
RA Elden A.C., Kim H.J., Hart M.P., Chen-Plotkin A.S., Johnson B.S.,
RA Fang X., Armakola M., Geser F., Greene R., Lu M.M., Padmanabhan A.,
RA Clay-Falcone D., McCluskey L., Elman L., Juhr D., Gruber P.J., Rub U.,
RA Auburger G., Trojanowski J.Q., Lee V.M., Van Deerlin V.M.,
RA Bonini N.M., Gitler A.D.;
RT "Ataxin-2 intermediate-length polyglutamine expansions are associated
RT with increased risk for ALS.";
RL Nature 466:1069-1075(2010).
RN [17]
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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [19]
RP STRUCTURE BY NMR OF 96-267.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the RNA binding domains of TAR DNA-binding
RT protein-43.";
RL Submitted (NOV-2005) to the PDB data bank.
RN [20]
RP STRUCTURE BY NMR OF 193-267.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of RRM domain in tar DNA-binding protein-43.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [21]
RP VARIANT ALS10 THR-315.
RX PubMed=18288693; DOI=10.1002/ana.21344;
RA Gitcho M.A., Baloh R.H., Chakraverty S., Mayo K., Norton J.B.,
RA Levitch D., Hatanpaa K.J., White C.L. III, Bigio E.H., Caselli R.,
RA Baker M., Al-Lozi M.T., Morris J.C., Pestronk A., Rademakers R.,
RA Goate A.M., Cairns N.J.;
RT "TDP-43 A315T mutation in familial motor neuron disease.";
RL Ann. Neurol. 63:535-538(2008).
RN [22]
RP VARIANT ALS10 ARG-343.
RX PubMed=18438952; DOI=10.1002/ana.21392;
RA Yokoseki A., Shiga A., Tan C.F., Tagawa A., Kaneko H., Koyama A.,
RA Eguchi H., Tsujino A., Ikeuchi T., Kakita A., Okamoto K.,
RA Nishizawa M., Takahashi H., Onodera O.;
RT "TDP-43 mutation in familial amyotrophic lateral sclerosis.";
RL Ann. Neurol. 63:538-542(2008).
RN [23]
RP VARIANTS ALS10 ALA-290 AND SER-298.
RX PubMed=18396105; DOI=10.1016/S1474-4422(08)70071-1;
RA Van Deerlin V.M., Leverenz J.B., Bekris L.M., Bird T.D., Yuan W.,
RA Elman L.B., Clay D., Wood E.M., Chen-Plotkin A.S., Martinez-Lage M.,
RA Steinbart E., McCluskey L., Grossman M., Neumann M., Wu I.-L.,
RA Yang W.-S., Kalb R., Galasko D.R., Montine T.J., Trojanowski J.Q.,
RA Lee V.M.-Y., Schellenberg G.D., Yu C.-E.;
RT "TARDBP mutations in amyotrophic lateral sclerosis with TDP-43
RT neuropathology: a genetic and histopathological analysis.";
RL Lancet Neurol. 7:409-416(2008).
RN [24]
RP VARIANTS ALS10 GLY-169; SER-287; THR-315; CYS-348; SER-361; THR-382;
RP ASP-390 AND SER-390, AND VARIANT VAL-90.
RX PubMed=18372902; DOI=10.1038/ng.132;
RA Kabashi E., Valdmanis P.N., Dion P., Spiegelman D., McConkey B.J.,
RA Vande Velde C., Bouchard J.-P., Lacomblez L., Pochigaeva K.,
RA Salachas F., Pradat P.-F., Camu W., Meininger V., Dupre N.,
RA Rouleau G.A.;
RT "TARDBP mutations in individuals with sporadic and familial
RT amyotrophic lateral sclerosis.";
RL Nat. Genet. 40:572-574(2008).
RN [25]
RP VARIANTS ALS10 ALA-294; LYS-331 AND VAL-337, VARIANT VAL-90, AND
RP CHARACTERIZATION OF VARIANTS ALS10 LYS-331 AND VAL-337.
RX PubMed=18309045; DOI=10.1126/science.1154584;
RA Sreedharan J., Blair I.P., Tripathi V.B., Hu X., Vance C., Rogelj B.,
RA Ackerley S., Durnall J.C., Williams K.L., Buratti E., Baralle F.,
RA de Belleroche J., Mitchell J.D., Leigh P.N., Al-Chalabi A.,
RA Miller C.C., Nicholson G., Shaw C.E.;
RT "TDP-43 mutations in familial and sporadic amyotrophic lateral
RT sclerosis.";
RL Science 319:1668-1672(2008).
RN [26]
RP INVOLVEMENT OF VARIANT ALS10 SER-295 IN FRONTOTEMPORAL LOBAR
RP DEGENERATION WITH MOTOR NEURON DISEASE.
RX PubMed=19350673; DOI=10.1002/ana.21612;
RG French clinical and genetic research network on frontotemporal lobar degeneration/frontotemporal lobar degeneration with motoneuron disease;
RA Benajiba L., Le Ber I., Camuzat A., Lacoste M., Thomas-Anterion C.,
RA Couratier P., Legallic S., Salachas F., Hannequin D., Decousus M.,
RA Lacomblez L., Guedj E., Golfier V., Camu W., Dubois B., Campion D.,
RA Meininger V., Brice A.;
RT "TARDBP mutations in motoneuron disease with frontotemporal lobar
RT degeneration.";
RL Ann. Neurol. 65:470-473(2009).
RN [27]
RP VARIANTS ALS10 SER-267; SER-287; VAL-294; SER-295; ARG-295; ASN-332;
RP ASP-335; VAL-337; PRO-379; CYS-379; THR-382 AND LEU-393.
RX PubMed=19224587; DOI=10.1002/humu.20950;
RA Corrado L., Ratti A., Gellera C., Buratti E., Castellotti B.,
RA Carlomagno Y., Ticozzi N., Mazzini L., Testa L., Taroni F.,
RA Baralle F.E., Silani V., D'Alfonso S.;
RT "High frequency of TARDBP gene mutations in Italian patients with
RT amyotrophic lateral sclerosis.";
RL Hum. Mutat. 30:688-694(2009).
RN [28]
RP INVOLVEMENT OF VARIANT ALS10 SER-267 IN FRONTOTEMPORAL DEMENTIA.
RX PubMed=19655382; DOI=10.1002/humu.21100;
RA Borroni B., Bonvicini C., Alberici A., Buratti E., Agosti C.,
RA Archetti S., Papetti A., Stuani C., Di Luca M., Gennarelli M.,
RA Padovani A.;
RT "Mutation within TARDBP leads to frontotemporal dementia without motor
RT neuron disease.";
RL Hum. Mutat. 30:E974-E983(2009).
RN [29]
RP VARIANT ALS10 ALA-294.
RX PubMed=19695877; DOI=10.1016/j.nmd.2009.07.005;
RA Luquin N., Yu B., Saunderson R.B., Trent R.J., Pamphlett R.;
RT "Genetic variants in the promoter of TARDBP in sporadic amyotrophic
RT lateral sclerosis.";
RL Neuromuscul. Disord. 19:696-700(2009).
RN [30]
RP VARIANT ALS10 THR-382.
RX PubMed=21220647; DOI=10.1001/archneurol.2010.352;
RA Chio A., Borghero G., Pugliatti M., Ticca A., Calvo A., Moglia C.,
RA Mutani R., Brunetti M., Ossola I., Marrosu M.G., Murru M.R.,
RA Floris G., Cannas A., Parish L.D., Cossu P., Abramzon Y.,
RA Johnson J.O., Nalls M.A., Arepalli S., Chong S., Hernandez D.G.,
RA Traynor B.J., Restagno G.;
RT "Large proportion of amyotrophic lateral sclerosis cases in Sardinia
RT due to a single founder mutation of the TARDBP gene.";
RL Arch. Neurol. 68:594-598(2011).
RN [31]
RP VARIANT ALS10 THR-382.
RX PubMed=21418058; DOI=10.1111/j.1399-0004.2011.01668.x;
RA Orru S., Manolakos E., Orru N., Kokotas H., Mascia V., Carcassi C.,
RA Petersen M.B.;
RT "High frequency of the TARDBP p.Ala382Thr mutation in Sardinian
RT patients with amyotrophic lateral sclerosis.";
RL Clin. Genet. 81:172-178(2012).
RN [32]
RP VARIANT VAL-90, AND VARIANTS ALS10 ARG-357; THR-361 AND PRO-379.
RX PubMed=22456481; DOI=10.1038/jhg.2012.24;
RA Chiang H.H., Andersen P.M., Tysnes O.B., Gredal O., Christensen P.B.,
RA Graff C.;
RT "Novel TARDBP mutations in Nordic ALS patients.";
RL J. Hum. Genet. 57:316-319(2012).
CC -!- FUNCTION: DNA and RNA-binding protein which regulates
CC transcription and splicing. Involved in the regulation of CFTR
CC splicing. It promotes CFTR exon 9 skipping by binding to the UG
CC repeated motifs in the polymorphic region near the 3'-splice site
CC of this exon. The resulting aberrant splicing is associated with
CC pathological features typical of cystic fibrosis. May also be
CC involved in microRNA biogenesis, apoptosis and cell division. Can
CC repress HIV-1 transcription by binding to the HIV-1 long terminal
CC repeat. Stabilizes the low molecular weight neurofilament (NFL)
CC mRNA through a direct interaction with the 3' UTR.
CC -!- SUBUNIT: Homodimer. Interacts with BRDT (By similarity). Binds
CC specifically to pyrimidine-rich motifs of TAR DNA and to single
CC stranded TG repeated sequences. Binds to RNA, specifically to UG
CC repeated sequences with a minimun of six contiguous repeats.
CC Interacts with ATNX2; the interaction is RNA-dependent.
CC -!- INTERACTION:
CC Self; NbExp=15; IntAct=EBI-372899, EBI-372899;
CC O43187:IRAK2; NbExp=2; IntAct=EBI-372899, EBI-447733;
CC -!- SUBCELLULAR LOCATION: Nucleus. Note=In patients with
CC frontotemporal lobar degeneration and amyotrophic lateral
CC sclerosis, it is absent from the nucleus of affected neurons but
CC it is the primary component of cytoplasmic ubiquitin-positive
CC inclusion bodies.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. In particular,
CC expression is high in pancreas, placenta, lung, genital tract and
CC spleen.
CC -!- DOMAIN: The RRM domains can bind to both DNA and RNA (By
CC similarity).
CC -!- PTM: Hyperphosphorylated in hippocampus, neocortex, and spinal
CC cord from individuals affected with ALS and FTLDU.
CC -!- PTM: Ubiquitinated in hippocampus, neocortex, and spinal cord from
CC individuals affected with ALS and FTLDU.
CC -!- PTM: Cleaved to generate C-terminal fragments in hippocampus,
CC neocortex, and spinal cord from individuals affected with ALS and
CC FTLDU.
CC -!- DISEASE: Amyotrophic lateral sclerosis 10 (ALS10) [MIM:612069]: A
CC neurodegenerative disorder affecting upper motor neurons in the
CC brain and lower motor neurons in the brain stem and spinal cord,
CC resulting in fatal paralysis. Sensory abnormalities are absent.
CC The pathologic hallmarks of the disease include pallor of the
CC corticospinal tract due to loss of motor neurons, presence of
CC ubiquitin-positive inclusions within surviving motor neurons, and
CC deposition of pathologic aggregates. The etiology of amyotrophic
CC lateral sclerosis is likely to be multifactorial, involving both
CC genetic and environmental factors. The disease is inherited in 5-
CC 10% of the cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 2 RRM (RNA recognition motif) domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=ABO32290.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact;
CC Sequence=ABO32292.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact;
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DR EMBL; U23731; AAA70033.1; -; mRNA.
DR EMBL; EF434181; ABO32290.1; ALT_SEQ; mRNA.
DR EMBL; EF434182; ABO32291.1; -; mRNA.
DR EMBL; EF434183; ABO32292.1; ALT_SEQ; mRNA.
DR EMBL; AK312416; BAG35326.1; -; mRNA.
DR EMBL; CR533534; CAG38565.1; -; mRNA.
DR EMBL; AK222754; BAD96474.1; -; mRNA.
DR EMBL; AL050265; CAB43367.1; -; mRNA.
DR EMBL; AL109811; CAI22098.1; -; Genomic_DNA.
DR EMBL; CH471130; EAW71670.1; -; Genomic_DNA.
DR EMBL; BC071657; AAH71657.1; -; mRNA.
DR EMBL; BC095435; AAH95435.1; -; mRNA.
DR PIR; I38977; I38977.
DR RefSeq; NP_031401.1; NM_007375.3.
DR UniGene; Hs.300624; -.
DR PDB; 1WF0; NMR; -; A=193-267.
DR PDB; 2CQG; NMR; -; A=96-185.
DR PDB; 4BS2; NMR; -; A=102-269.
DR PDBsum; 1WF0; -.
DR PDBsum; 2CQG; -.
DR PDBsum; 4BS2; -.
DR ProteinModelPortal; Q13148; -.
DR SMR; Q13148; 55-267.
DR DIP; DIP-31167N; -.
DR IntAct; Q13148; 23.
DR MINT; MINT-5002768; -.
DR STRING; 9606.ENSP00000240185; -.
DR ChEMBL; CHEMBL2362981; -.
DR PhosphoSite; Q13148; -.
DR DMDM; 20140568; -.
DR PaxDb; Q13148; -.
DR PRIDE; Q13148; -.
DR DNASU; 23435; -.
DR Ensembl; ENST00000240185; ENSP00000240185; ENSG00000120948.
DR GeneID; 23435; -.
DR KEGG; hsa:23435; -.
DR UCSC; uc001art.3; human.
DR CTD; 23435; -.
DR GeneCards; GC01P011006; -.
DR HGNC; HGNC:11571; TARDBP.
DR HPA; CAB003703; -.
DR HPA; HPA017284; -.
DR MIM; 605078; gene.
DR MIM; 612069; phenotype.
DR neXtProt; NX_Q13148; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease.
DR PharmGKB; PA36336; -.
DR eggNOG; COG0724; -.
DR HOVERGEN; HBG058671; -.
DR InParanoid; Q13148; -.
DR OMA; KHNSSRQ; -.
DR PhylomeDB; Q13148; -.
DR ChiTaRS; TARDBP; human.
DR EvolutionaryTrace; Q13148; -.
DR GeneWiki; TARDBP; -.
DR GenomeRNAi; 23435; -.
DR NextBio; 45695; -.
DR PRO; PR:Q13148; -.
DR ArrayExpress; Q13148; -.
DR Bgee; Q13148; -.
DR CleanEx; HS_TARDBP; -.
DR Genevestigator; Q13148; -.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:BHF-UCL.
DR GO; GO:0003730; F:mRNA 3'-UTR binding; IDA:BHF-UCL.
DR GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0070935; P:3'-UTR-mediated mRNA stabilization; IDA:BHF-UCL.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0006397; P:mRNA processing; IEA:UniProtKB-KW.
DR GO; GO:0043922; P:negative regulation by host of viral transcription; IDA:BHF-UCL.
DR GO; GO:0008380; P:RNA splicing; IDA:BHF-UCL.
DR GO; GO:0006366; P:transcription from RNA polymerase II promoter; TAS:ProtInc.
DR Gene3D; 3.30.70.330; -; 2.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait.
DR InterPro; IPR000504; RRM_dom.
DR Pfam; PF00076; RRM_1; 2.
DR SMART; SM00360; RRM; 2.
DR PROSITE; PS50102; RRM; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Amyotrophic lateral sclerosis; Complete proteome;
KW Direct protein sequencing; Disease mutation; DNA-binding;
KW mRNA processing; mRNA splicing; Neurodegeneration; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat; Repressor;
KW RNA-binding; Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1 414 TAR DNA-binding protein 43.
FT /FTId=PRO_0000081972.
FT DOMAIN 104 200 RRM 1.
FT DOMAIN 191 262 RRM 2.
FT COMPBIAS 274 413 Gly-rich.
FT MOD_RES 292 292 Phosphoserine.
FT VARIANT 90 90 A -> V (in dbSNP:rs80356715).
FT /FTId=VAR_045656.
FT VARIANT 169 169 D -> G (in ALS10; dbSNP:rs80356717).
FT /FTId=VAR_045657.
FT VARIANT 267 267 N -> S (in ALS10; also in a patient with
FT frontotemporal dementia;
FT dbSNP:rs80356718).
FT /FTId=VAR_058611.
FT VARIANT 287 287 G -> S (in ALS10; dbSNP:rs80356719).
FT /FTId=VAR_045658.
FT VARIANT 290 290 G -> A (in ALS10; dbSNP:rs121908395).
FT /FTId=VAR_045659.
FT VARIANT 294 294 G -> A (in ALS10; dbSNP:rs80356721).
FT /FTId=VAR_045660.
FT VARIANT 294 294 G -> V (in ALS10; a patient with bulbar
FT signs and dementia).
FT /FTId=VAR_058612.
FT VARIANT 295 295 G -> R (in ALS10; dbSNP:rs80356723).
FT /FTId=VAR_058613.
FT VARIANT 295 295 G -> S (in ALS10; also in patients with
FT frontotemporal lobar degeneration with
FT motor neuron disease; dbSNP:rs80356723).
FT /FTId=VAR_058614.
FT VARIANT 298 298 G -> S (in ALS10; dbSNP:rs4884357).
FT /FTId=VAR_045661.
FT VARIANT 315 315 A -> T (in ALS10; dbSNP:rs80356726).
FT /FTId=VAR_045662.
FT VARIANT 331 331 Q -> K (in ALS10; impedes the development
FT of normal limb and tail buds and
FT increases the number of apoptotic nuclei
FT when expressed in chick embryos; does not
FT affect the interaction with ATNX2;
FT dbSNP:rs80356727).
FT /FTId=VAR_045663.
FT VARIANT 332 332 S -> N (in ALS10; dbSNP:rs80356728).
FT /FTId=VAR_058615.
FT VARIANT 335 335 G -> D (in ALS10; dbSNP:rs80356729).
FT /FTId=VAR_058616.
FT VARIANT 337 337 M -> V (in ALS10; impedes the development
FT of normal limb and tail buds and
FT increases the number of apoptotic nuclei
FT when expressed in chick embryos;
FT dbSNP:rs80356730).
FT /FTId=VAR_045664.
FT VARIANT 343 343 Q -> R (in ALS10; dbSNP:rs80356731).
FT /FTId=VAR_062767.
FT VARIANT 348 348 G -> C (in ALS10; dbSNP:rs80356733).
FT /FTId=VAR_045665.
FT VARIANT 357 357 G -> R (in ALS10).
FT /FTId=VAR_067499.
FT VARIANT 361 361 R -> S (in ALS10; dbSNP:rs80356735).
FT /FTId=VAR_045666.
FT VARIANT 361 361 R -> T (in ALS10).
FT /FTId=VAR_067500.
FT VARIANT 379 379 S -> C (in ALS10; dbSNP:rs80356739).
FT /FTId=VAR_058617.
FT VARIANT 379 379 S -> P (in ALS10; dbSNP:rs80356738).
FT /FTId=VAR_058618.
FT VARIANT 382 382 A -> T (in ALS10; dbSNP:rs11689432).
FT /FTId=VAR_045667.
FT VARIANT 390 390 N -> D (in ALS10; dbSNP:rs80356741).
FT /FTId=VAR_045668.
FT VARIANT 390 390 N -> S (in ALS10; dbSNP:rs80356742).
FT /FTId=VAR_045669.
FT VARIANT 393 393 S -> L (in ALS10; dbSNP:rs80356743).
FT /FTId=VAR_058619.
FT MUTAGEN 106 175 Missing: Completely abolishes RNA
FT binding.
FT MUTAGEN 106 111 LIVLGL->DIDLGD: Completely abolishes RNA
FT binding.
FT MUTAGEN 106 111 Missing: Completely abolishes RNA
FT binding.
FT MUTAGEN 147 149 FGF->LGL: Highly reduces binding to RNA
FT and DNA.
FT MUTAGEN 193 257 Missing: Alters but does not abolish RNA
FT binding.
FT CONFLICT 200 200 E -> G (in Ref. 5; BAD96474).
FT CONFLICT 278 278 G -> V (in Ref. 3; BAG35326).
FT STRAND 106 110
FT HELIX 117 124
FT HELIX 125 127
FT STRAND 130 137
FT STRAND 139 141
FT STRAND 143 154
FT HELIX 155 163
FT STRAND 166 168
FT STRAND 171 176
FT STRAND 193 197
FT STRAND 200 202
FT HELIX 204 210
FT TURN 212 214
FT STRAND 219 221
FT STRAND 231 233
FT HELIX 237 242
FT TURN 243 245
FT STRAND 247 250
FT STRAND 253 258
SQ SEQUENCE 414 AA; 44740 MW; 8E09A1206FB4EF4A CRC64;
MSEYIRVTED ENDEPIEIPS EDDGTVLLST VTAQFPGACG LRYRNPVSQC MRGVRLVEGI
LHAPDAGWGN LVYVVNYPKD NKRKMDETDA SSAVKVKRAV QKTSDLIVLG LPWKTTEQDL
KEYFSTFGEV LMVQVKKDLK TGHSKGFGFV RFTEYETQVK VMSQRHMIDG RWCDCKLPNS
KQSQDEPLRS RKVFVGRCTE DMTEDELREF FSQYGDVMDV FIPKPFRAFA FVTFADDQIA
QSLCGEDLII KGISVHISNA EPKHNSNRQL ERSGRFGGNP GGFGNQGGFG NSRGGGAGLG
NNQGSNMGGG MNFGAFSINP AMMAAAQAAL QSSWGMMGML ASQQNQSGPS GNNQNQGNMQ
REPNQAFGSG NNSYSGSNSG AAIGWGSASN AGSGSGFNGG FGSSMDSKSS GWGM
//

MIM 605078
*RECORD*
*FIELD* NO
605078
*FIELD* TI
*605078 TAR DNA-BINDING PROTEIN; TARDBP
;;TAR DNA-BINDING PROTEIN, 43-KD; TDP43
*FIELD* TX
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DESCRIPTION

The TARDBP gene encodes the 43-kD TAR DNA-binding protein, which was
originally identified as a transcriptional repressor that binds to TAR
DNA of human immunodeficiency virus type 1. It is also involved in
regulation of gene expression and splicing (summary by Benajiba et al.,
2009).

CLONING

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS),
contains an RNA genome that produces a chromosomally integrated DNA
during the replicative cycle. The HIV Tat protein (see 601409), a
transcription-activating protein that binds to the bulge region of a
stable stem-bulge-loop structure, TAR RNA, activates the HIV-1 long
terminal repeat (LTR). Tat activates the LTR less efficiently in rodent
than in human cells, suggesting that cellular RNA-binding proteins are
also involved in the regulation of HIV replication. TAR DNA may possess
distinct regulatory elements that play a role in modulating HIV-1 gene
expression. To characterize cellular factors that bind to TAR DNA, Ou et
al. (1995) screened a HeLa cell cDNA library using a TAR DNA probe and
identified a cDNA encoding a 43-kD TAR DNA-binding protein, TARDBP,
which they called TDP43. The deduced 414-amino acid TARDBP contains a
ribonucleoprotein (RNP)-binding domain and a glycine-rich region.
Northern blot analysis detected a ubiquitously expressed, 2.8-kb TARDBP
transcript. SDS-PAGE analysis showed that recombinant and native TARDBP
are expressed as 43-kD proteins.

By database analysis and cDNA cloning, Wang et al. (2004) determined
that the TARDBP gene generates at least 11 mRNA species by alternative
splicing. The shorter transcripts encode proteins lacking the
glycine-rich domain, which is required for the exon-skipping activity of
TARDBP.

Benajiba et al. (2009) stated that TDP43 contains 2 RNA recognition
motifs, a nuclear export domain, and a C-terminal domain that is
essential for binding to heterogeneous nuclear ribonucleoproteins
(hnRNPs) and for splicing inhibition. TDP43 is normally localized in the
nucleus, but in pathologic conditions, the cleaved form of TDP43 is
mainly present in the cytoplasm

GENE STRUCTURE

Wang et al. (2004) determined that the TARDBP gene contains 6 exons.

MAPPING

By genomic sequence analysis, Wang et al. (2004) mapped the TARDBP gene
to chromosome 1p36.21. They also identified intronless TARDBP-like
pseudogenes on chromosomes 2, 6, 8, 13, and 20 that likely originated
from retrotransposition events. Wang et al. (2004) mapped the mouse
Tardbp gene to chromosome 4E2 in a region that shows homology of synteny
to human chromosome 1p36.

GENE FUNCTION

Functional analysis by Ou et al. (1995) indicated that TARDBP does not
bind RNA. Gel retardation analysis followed by Western blot analysis
(Shift-Western analysis) demonstrated that the RNP-binding motifs of
TARDBP bind to the pyrimidine-rich motifs of TAR DNA. In an in vitro
transcription analysis, increasing amounts of TARDBP, in the presence or
absence of Tat, decreased the level of transcription from the HIV-1 LTR
but not from the adenovirus major late promoter.

Using reporter plasmids, Wang et al. (2004) determined that deletion of
the glycine-rich domain of mouse Tardbp resulted in loss of about 90% of
its ability to activate exon skipping in the CFTR gene (602421).

RNA splicing mutations in the CFTR gene are thought to lead to
dysfunction of several organs such as lung, sweat glands, genital tract,
intestine and pancreas, producing the complex symptoms of cystic
fibrosis (219700). Buratti et al. (2001) showed that TDP43 promotes
skipping of exon 9 of the CFTR gene by binding specifically to the UG
repeat sequence in intron 8 of the CFTR pre-mRNA. Buratti and Baralle
(2001) reported the characterization and functional implications of the
RNA binding properties of TDP43. Wang et al. (2004) found that the mouse
homolog of human TDP43 also inhibits human CFTR exon 9 splicing in a
minigene system. Buratti et al. (2004) described experiments consistent
with the model in which the TG repeats in the CFTR intron 8 bind to
TDP43, and this protein, in turn, inhibits splicing of exon 9. They
suggested that their results provide a mechanistic explanation for the
association data of Groman et al. (2004) and also an explanation for the
variable phenotypic penetrance of the TG repeats. Individual and
tissue-specific variability in the concentration of this inhibitory
splicing factor may even determine whether an individual will develop
multisystemic (non-classic CF) or monosymptomatic (CBAVD) disease.

Neumann et al. (2006) found that a hyperphosphorylated, ubiquitinated,
and cleaved form of TDP43, known as pathologic TDP43, is the major
disease protein in ubiquitin-positive, tau-, and
alpha-synuclein-negative frontotemporal dementia (FTLD-U; 607485) and in
ALS (see 105400). The signature of pathologic TDP43 in FTLD-U includes
the presence of C-terminal breakdown and/or cleavage products migrating
at approximately 25 kD, a 45 kD variant, and a high molecular weight
TDP43-immunoreactive smear. TDP43 is normally localized primarily to the
nucleus, but Neumann et al. (2006) suggested that, under pathologic
conditions in FTLD-U, TDP43 is eliminated from nuclei of ubiquitinated
inclusion-bearing neurons, a consequence of which may be a loss of TDP43
nuclear functions.

Mackenzie et al. (2007) identified TDP43-immunoreactive neuronal and
glial cytoplasmic inclusions in 59 cases of sporadic ALS, 26 cases of
ALS with dementia, and 11 cases of SOD1 (147450)-negative familial ALS.
Immunofluorescence confirmed colocalization of TDP43 and ubiquitin
within the inclusions. In contrast, TDP43 was not detected in any of 15
patients with SOD1-positive ALS. The authors suggested that these
findings represented differing pathogenic mechanisms.

Elden et al. (2010) showed that ataxin-2 (601517), a polyglutamine
(polyQ) protein mutated in spinocerebellar ataxia type 2 (183090), is a
potent modifier of TDP43 toxicity in animal and cellular models of ALS
(105400). ATXN2 and TDP43 associate in a complex that depends on RNA. In
spinal cord neurons of ALS patients, ATXN2 is abnormally localized;
likewise, TDP43 shows mislocalization in spinocerebellar ataxia-2. To
assess the involvement of ATXN2 in ALS, Elden et al. (2010) analyzed the
length of the polyQ repeat in the ATXN2 gene in 915 ALS patients and 980
controls. The authors found that intermediate-length polyQ expansions
(27 to 33 glutamines) in ATXN2 were significantly associated with ALS
(4.7% of cases; 1.4% of controls).

Armakola et al. (2012) reported results from 2 genomewide
loss-of-function TDP43 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

Lattante et al. (2013) provided a review of TARDBP mutations associated
with ALS10. TARDPB mutations occur in about 3% of patients with familial
ALS and in 1.5% of patients with sporadic disease.

Gitcho et al. (2009) noted that TDP43 was first identified as the major
pathologic protein of ubiquitin-positive, tau-negative inclusions of
frontotemporal lobar degeneration (FTLDU; 607485), FTLD with motor
neuron disease (FTDMND; 105500), and ALS/MND (ALS10; 612069). These
disorders are now considered to represent different clinical
manifestations of the same underlying molecular pathology, namely TDP43
proteinopathy. The differing clinical phenotypes of these overlapping
disorders most likely reflect the selective vulnerability of different
segments of the neuraxis to neurodegeneration.

In a family segregating autosomal dominant ALS and 2 sporadic cases (see
ALS10, 612069), Sreedharan et al. (2008) identified mutations in the
TARDBP gene. All 3 mutations, M337V (605078.0001), Q331K (605078.0002),
and G294A (605078.0001) occurred in a highly conserved region of the C
terminus of TDP43 involved in protein-protein interactions. To assess
the functional significance of these mutations, Sreedharan et al. (2008)
expressed tagged TDP43(wildtype), TDP43(Q331K), and TDP43(M337V) in
Chinese hamster ovary (CHO) cells. Immunofluorescent staining of cells
48 hours after transfection showed abundant expression of transfected
TDP43, with no obvious differences in subcellular distribution or
aggregation between mutant and wildtype proteins. Expression of these
tagged proteins in spinal cord of stage 14 chick embryos demonstrated
dramatic reduction in maturation in embryos expressing mutant versus
wildtype TDP43, with a failure to develop normal limb and tail buds.
While chick embryo development proceeded normally over 48 hours with
TDP43(wildtype), at 24 hours only 5 to 15% of those embryos expressing
mutant TDP43 had reached the normal stage of maturation. TUNEL staining
demonstrated a significant increase in the number of apoptotic nuclei in
embryos expressing either mutant when compared with wildtype. Sreedharan
et al. (2008) concluded that their results suggested a toxic
gain-of-function or dominant-negative effect of mutant TDP43.

In affected members of a Japanese family with ALS previously described
by Tagawa et al. (2007), Yokoseki et al. (2008) identified a
heterozygous mutation in the TARDBP gene (Q343R; 605078.0008).

In affected members of a European family with ALS10, Gitcho et al.
(2008) identified a heterozygous mutation in the TARDBP gene (A315T;
605078.0009).

Van Deerlin et al. (2008) identified heterozygous mutations in the
TARDBP gene (605078.0004; 605078.0005) in affected individuals of 2
unrelated families with autosomal dominant ALS10.

Kabashi et al. (2008) screened a panel of familial and sporadic ALS
cases for TARDBP mutations. They found 8 missense mutations in 9
individuals, 6 from individuals with sporadic ALS and 3 from those with
familial ALS, and a concurring increase of a smaller TDP43 product.

By sequence analysis, Kabashi et al. (2009) did not find any pathogenic
mutations in the TARDBP gene among 125 French Canadian patients with
dopa-responsive Parkinson disease (PD; 168600).

Kuhnlein et al. (2008) identified mutations in the TARDBP gene in 2
(6.5%) of 31 probands with non-SOD1 familial ALS.

Kovacs et al. (2009) identified a heterozygous mutation in the TARDBP
gene (K263E; 605078.0011) in a Hungarian man with frontotemporal lobar
degeneration beginning at age 35 years. He had a rapidly progressive
course, resulting in death at age 37., Neurologic examination showed
supranuclear gaze palsy, hyperkinetic choreiform movements, motor
stereotypies, and primitive reflexes. Motor neuron disease signs,
rigidity, and cerebellar ataxia were not present.
Phospho-TDP43-immunoreactive deposits were present in neuronal
cytoplasmic inclusions in various brain regions, including the cortex,

Gitcho et al. (2009) identified a heterozygous 2076G-A transition in the
3-prime untranslated region of the TARDBP gene (605078.0012) in affected
members of 2 unrelated families with either ALS10 with or without
frontotemporal dementia or FTLD (see 612069). The first family had 2
mutation carriers with a variable phenotype: the proband was a woman
with frontotemporal dementia without motor disease, whereas her brother
had lower motor neuron disease without dementia. The father and mother,
from whom DNA was not available, had ALS and lower motor neuron disease,
respectively, and it was not clear which parent likely transmitted the
TARDBP mutation. Neuropathologic analysis of the proband, who did not
have motor neuron disease, showed cortical atrophy, neuronal loss in the
hippocampus, hippocampal sclerosis, and TDP43-positive neuronal
cytoplasmic inclusions in the cortex and hippocampus. The brother's
neuropathologic findings were consistent with ALS and showed
TDP43-immunoreactivity in the anterior horn cells of the spinal cord and
neuronal cytoplasmic inclusions in the hippocampus. The second family
included a patient with familial ALS; no neuropathology was available
for that patient.

Millecamps et al. (2010) identified 6 different missense mutations in
the TARDBP gene in 7 (4.3%) of 162 French probands with familial ALS.
Three of the families had been previously reported. Patients with TARDBP
mutations had disease onset predominantly in the upper limb. One-third
of patients had rapid disease progression, two-thirds had a medium
disease course, and 1 had a slow disease course. There was evidence of
incomplete penetrance. One TARDBP mutation carrier developed
frontotemporal dementia 1 year after the onset of motor weakness.

Kabashi et al. (2010) tested the effects of 3 reported TARDBP mutations,
A315T, (605078.0009), G348C (605078.0007), and A382T (605078.0013), in
cell lines, primary cultured motor neurons, and living zebrafish
embryos. Each of the 3 mutants and wildtype human TDP43 localized to
nuclei when expressed in COS-1 and Neuro2A cells by transient
transfection. However, when expressed in motor neurons from dissociated
spinal cord cultures, these mutant TARDBP alleles were neurotoxic,
concomitant with perinuclear localization and aggregation of TDP43.
Overexpression of mutant human TARDBP caused a motor phenotype in
zebrafish embryos consisting of shorter motor neuronal axons, premature
and excessive branching, as well as swimming deficits. Knockdown of
zebrafish Tardbp led to a similar phenotype, which was rescued by
coexpressing wildtype but not mutant human TARDBP. Kabashi et al. (2010)
suggested that both a toxic gain of function as well as a novel loss of
function may be involved in the molecular mechanism by which mutant
TDP43 contributes to disease pathogenesis.

GENOTYPE/PHENOTYPE CORRELATIONS

Corcia et al. (2012) identified 19 patients from 9 families with ALS10
and 9 patients with apparently sporadic ALS10. The patients were French,
and all carried mutations in the TARDBP gene. The mean age at onset was
53.4 years, and the upper limb was the most common site of onset. Only 2
patients had dementia. The median disease duration was 63 months; 2
patients were alive after 8 years. These patients were pooled with 117
ALS10 patients reported in the literature. Among all those with TARDBP
mutations, Caucasians tended to have upper limb onset, while Asians
tended to have bulbar onset. The G298S mutation (605078.0005) was
associated with the shortest survival, whereas A315T (605078.0009) and
M337V (605078.0001) were associated with longest duration.

By expression of 7 pathogenic ALS-associated mutant TDP43 proteins
(e.g., M337V, 605078.0001; A382T, 605078.0013; G298S, 605078.0005;
G348C, 605078.0007; Q343R, 605078.0008; and A315T, 605078.0009) in a
differentiated neuronal cell line, Watanabe et al. (2013) found that all
had consistently longer half-lives compared to the wildtype protein.
Patients carrying mutations with longer half-lives showed earlier
disease onset (p = 0.00252), although there was no correlation between
protein half-lives and disease duration. Proteins with mutations in the
nuclear export signal had an extremely long half-life, whereas a second
group of mutations generated within the nuclear localization signal were
less stable than wildtype. In additional studies, most of 18 ALS-linked
mutant TDP43 proteins showed lower solubility to the detergent Sarkosyl
compared to wildtype. A cell model in which wildtype TDP43 was
stabilized caused cytotoxicity, nuclear accumulation, insolubility,
proteasomal impairment with increased numbers of misfolded C-terminal
cleaved TDP43 products, and dysregulation of normal mRNA processing. The
findings suggested that increased stability of either wildtype or mutant
TDP43 can cause a gain of toxicity through abnormal proteostasis.

ANIMAL MODEL

Wegorzewska et al. (2009) found that transgenic mice expressing a Tdp43
A315T mutation (605078.0009) developed progressive gait abnormalities at
about 3 to 4 months of age and died at about 5 months of age. Postmortem
examination showed accumulation of ubiquitinated proteins selectively in
the cytoplasm of neurons in cortical layer 5, including the motor
cortex. The inclusions did not stain for TDP43, but the changes were
associated with neuronal loss and increased glial reaction. Examination
of the spinal cord of mutant mice showed degeneration of descending
motor axons and ubiquitin pathology in large neurons of the ventral
horn; there was also loss of motor neurons. Mutant mice also showed
Tdp43 C-terminal fragments in the brain and spinal cord prior to the
onset of gait abnormalities. Wegorzewska et al. (2009) concluded that
since cytoplasmic Tdp43 aggregates were not present in mutant mice, they
are not required for neurodegeneration. These results indicated that the
selective neuronal vulnerability in Tdp43-related neurodegeneration is
related to altered DNA/RNA-binding protein function rather than to toxic
aggregation.

Tsai et al. (2010) generated an FTLDU mouse model by transgenically
overexpressing Tdp43 in forebrain. Transgenic mice exhibited impaired
learning and memory, progressive motor dysfunction, and hippocampal
atrophy. The impairments were accompanied by reduced levels of
phosphorylated Erk (see MAPK1; 176948) and phosphorylated Creb (CREB1;
123810) and increased levels of gliosis in the brains of transgenic
mice. Cells with Tdp43-positive, ubiquitin-positive neuronal cytoplasmic
inclusions (NCIs) and Tdp43-deleted nuclei appeared in transgenic mouse
brains in an age-dependent manner. Tsai et al. (2010) concluded that
increased levels of TDP43 protein in forebrain are sufficient to lead to
formation of TDP43-positive, ubiquitin-positive NCIs and
neurodegeneration.

Independently, Wils et al. (2010) observed neurodegeneration in
transgenic mice overexpressing wildtype human TDP43. Homozygous and
hemizygous transgenic mice showed dose-dependent degeneration of
cortical and spinal motor neurons and developed spastic quadriplegia
similar to ALS. Transgenic mice also developed dose-dependent
degeneration of nonmotor cortical and subcortical neurons characteristic
of FTLD. Affected neurons of the spinal cord and brain showed nuclear
and cytoplasmic aggregates of ubiquitinated and phosphorylated TDP43.
The characteristic, approximately 25-kD TDP43 C-terminal fragments were
also recovered from nuclear fractions and correlated with disease
development and progression in transgenic mice.

Ash et al. (2010) engineered panneuronal expression of human TDP43 in C.
elegans to generate an in vivo model of TDP43 function and
neurotoxicity. Transgenic worms with neuronal expression of human TDP43
exhibited an 'uncoordinated' phenotype and had abnormal motoneuron
synapses. C. elegans contains a single putative ortholog of TDP43,
designated tdp1, which could support alternative splicing of CFTR
(602421) in a cell-based assay. Neuronal overexpression of tdp1 also
resulted in an uncoordinated phenotype, whereas deletion of the tdp1
gene did not affect movement or alter motoneuron synapses. Wildtype
human TDP43 expressed in C. elegans localized to the nucleus. TDP43
mutants missing either RNA recognition domain RRM1 or RRM2 completely
blocked neurotoxicity, as did a mutant missing its C-terminal domain.
These TDP43 mutants still accumulated in the nucleus, although their
subnuclear distribution was altered. Fusion of the tdp1 C-terminal
domain to a TDP43 N terminus restored normal subnuclear localization and
toxicity in C. elegans and CFTR splicing in cell-based assays.
Overexpression of wildtype TDP43 in differentiated M17 cells also
resulted in cell toxicity. Ash et al. (2010) concluded that
overexpression of wildtype TDP43 is sufficient to induce neurotoxicity.

*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, MET337VAL

In an English family segregating autosomal dominant amyotrophic lateral
sclerosis without frontotemporal dementia (612069), Sreedharan et al.
(2008) identified an A-to-G transition at nucleotide 1009 in exon 6 of
the TARDBP gene, resulting in a methionine-to-valine substitution at
codon 337 (M337V). Methionine at this position is invariant in human,
orangutan, mouse, opossum, chicken, frog, and zebrafish.

.0002
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, GLN331LYS

In a 72-year-old Caucasian British man who developed limb-onset ALS
(612069) with a disease duration of 3 years, Sreedharan et al. (2008)
identified a C-to-A transversion at nucleotide 991 in exon 6 of the
TARDBP gene, resulting in a glutamine-to-lysine substitution at codon
331 (Q331K).

.0003
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, GLY294ALA

In an Australian man who developed limb-onset ALS (612069) at age 65
with a disease duration of 5 years and no atypical features, Sreedharan
et al. (2008) identified a G-to-C transversion at nucleotide 881 in exon
6 of the TARDBP gene, resulting in a glycine-to-alanine substitution at
codon 294 (G294A).

Luquin et al. (2009) identified the G294A mutation in postmortem brain
tissue from a patient with sporadic ALS. No clinical information was
given.

.0004
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, GLY290ALA

In a Caucasian father and daughter with autosomal dominant ALS10
(612069), Van Deerlin et al. (2008) identified a heterozygous 869G-C
transversion in exon 6 of the TARDBP gene, resulting in a gly290-to-ala
(G290A) substitution in the C-terminal region of TDP43. The mutation was
not identified in 747 white controls. The daughter presented with
dysarthria and dysphagia at age 51 years and had a rapidly progressive
course involving the limbs and respiration. She died after 13 months.
Her father had presented with arm weakness at age 47 years and died
after 16 months. Postmortem examination showed findings consistent with
ALS.

.0005
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, GLY298SER

In affected members of a Chinese family with autosomal dominant ALS10
(612069), Van Deerlin et al. (2008) identified a heterozygous 892G-A
transition in exon 6 of the TARDBP gene, resulting in a gly298-to-ser
(G298S) substitution in the C-terminal region of TDP43. The mutation was
not identified in 747 white controls or 380 Chinese controls. Five
patients in 2 generations were affected with onset between ages 41 and
60 years. Most showed rapid progression with death within 1 or 2 years.
Postmortem examination of 2 patients showed changes consistent with ALS
as well as TDP43-positive inclusions in upper and lower motor neurons
and in various brain regions.

.0006
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, ASP169GLY

In a 56-year-old female with amyotrophic lateral sclerosis (612069),
Kabashi et al. (2008) found a heterozygous A-to-G transition in exon 4
of the TARDBP gene (640A-G) that resulted in an asp169-to-gly
substitution (D169G) in TDP43. The mutation occurred in the first RNA
recognition motif (RRM1) and was predicted to abrogate RNA binding.

.0007
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, GLY348CYS

In a 30-year-old female patient with amyotrophic lateral sclerosis
(612069), Kabashi et al. (2008) detected a heterozygous G-to-T
transversion at nucleotide 1176 in exon 6 of the TARDBP gene that
resulted in substitution of cys for gly at codon 348 of TDP43 (G348C).
The mutation, which introduced a cysteine to the C-terminal hnRNP
interaction region, was predicted to increase the propensity for
aggregation through the formation of intermolecular disulfide bridges.

Kuhnlein et al. (2008) identified the G348C mutation in affected members
of a German family with ALS10. The proband presented at age 55 years
with paresis of the right hand, which progressed rapidly to involve the
arms and lower limbs and left her wheelchair-bound within 2.5 years. She
died of respiratory insufficiency 3 years after disease onset. The
patient's mother had died of respiratory insufficiency due to a similar
disorder. There were no clinically relevant bulbar symptoms and no
cognitive impairment.

.0008
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, GLN343ARG

In affected members of a Japanese family with amyotrophic lateral
sclerosis (612069), Yokoseki et al. (2008) identified heterozygosity for
a 1028A-G transition in the TARDBP gene, resulting in a gln343-to-arg
(Q343R) substitution. The mutation occurs in a highly conserved residue
and was not present in 534 chromosomes in Japanese control subjects.

.0009
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND
WITH TDP43 INCLUSIONS
TARDBP, ALA315THR

In affected members of a European family with amyotrophic lateral
sclerosis (612069), Gitcho et al. (2008) identified heterozygosity for a
1077G-A transition in exon 6 of the TARDBP gene, resulting in an
ala315-to-thr substitution. The mutation occurs in a highly conserved
residue and was not found in 1,505 ethnically matched elderly control
subjects.

.0010
AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
AND WITH TDP43 INCLUSIONS
TARDBP, GLY295SER

In a woman with ALS10 (612069), Benajiba et al. (2009) identified a
heterozygous 883G-A transition in exon 6 of the TARDBP gene, resulting
in a gly295-to-ser (G295S) substitution in the hnRNP-binding domain. She
also developed semantic frontotemporal dementia. Her sister, who carried
the mutation, and their deceased father, who presumably carried the
mutation, both had motor neuron disease without dementia. The G295S
mutation was also identified in an unrelated woman with the behavioral
variant of frontotemporal dementia and motor neuron disease. The
mutation was not found in 400 control individuals.

.0011
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED
TARDBP, LYS263GLU

In a Hungarian man with frontotemporal lobar degeneration (see 612069),
Kovacs et al. (2009) identified a heterozygous A-to-G transition in exon
6 of the TARDBP gene, resulting in a lys263-to-glu (K263E) substitution
in the highly conserved C terminus. The mutation was not found in 530
controls. The patient developed personality changes beginning at age 35
years. This was followed by a rapid deterioration in attention and
thinking, with psychomotor agitation and insomnia, consistent with FTD.
Neurologic examination showed supranuclear gaze palsy, hyperkinetic
choreiform movements, motor stereotypies, and primitive reflexes. Motor
neuron disease signs, rigidity, and cerebellar ataxia were not present.
He died at age 37 years of pulmonary edema secondary to cardiac failure.
Neuropathologic examination neuronal loss and astrogliosis in the
subcortical gray matter. Phospho-TDP43-immunoreactive deposits were
present in neuronal cytoplasmic inclusions in various brain regions,
including the cortex, basal ganglia, thalamus, and brainstem. The
findings indicated that TARDBP mutations can be associated with a wider
clinicopathologic spectrum of disorders than originally thought.

.0012
AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
AND WITH TDP43 INCLUSIONS
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED
TARDBP, 2076G-A, 3-PRIME UTR

In affected members of 2 unrelated families with either ALS10 with or
without frontotemporal dementia (612069) or FTLD (see 612069), Gitcho et
al. (2009) identified a heterozygous 2076G-A transition in the 3-prime
untranslated region of the TARDBP gene adjacent to the last exon, exon
6. The first family had 2 mutation carriers with a variable phenotype:
the proband was a woman with frontotemporal dementia without motor
disease, whereas her brother had lower motor neuron disease without
dementia. The father and mother, from whom DNA was not available, had
ALS and lower motor neuron disease, respectively, and it was not clear
which parent likely transmitted the TARDBP mutation. Neuropathologic
analysis of the proband, who did not have motor neuron disease, showed
cortical atrophy, neuronal loss in the hippocampus, hippocampal
sclerosis, and TDP43-positive neuronal cytoplasmic inclusions in the
cortex and hippocampus. There was no evidence of motor neuron loss from
the motor nuclei of the brainstem. The brother's neuropathologic
findings were consistent with ALS and showed TDP43-immunoreactivity in
the anterior horn cells of the spinal cord and neuronal cytoplasmic
inclusions in the hippocampus. The second family included a patient with
familial ALS; no neuropathology was available for that patient. The
2076G-A variant is highly conserved across species, suggesting
functional importance, and was not found in 974 control individuals.
Allele-specific functional analysis showed that the 2076G-A variant was
associated with a 2-fold increase in TARDBP expression. These findings
suggested that a common molecular pathology can result in clinically
heterogeneous phenotypes.

.0013
AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
AND WITH TDP43 INCLUSIONS
TARDBP, ALA382THR

In 7 Italian probands with ALS10 (612069), Corrado et al. (2009)
identified a heterozygous 1144G-A transition in exon 6 of the TARDBP
gene, resulting in an ala382-to-thr (A382T) substitution. The patients
were identified from a larger cohort of 666 Italian ALS patients. A382T
was the most common of all TARDBP mutations and was found in 6 of 18
probands. All the patients had ALS with predominantly lower motor neuron
disease affecting the upper limb, with proximal spreading; none had
cognitive impairment. Haplotype analysis indicated a founder effect in 5
of 7 patients with the A382T mutation. Lymphocyte studies showed
accumulation of aberrant TARDBP bands, suggesting instability of the
mutant protein.

Chio et al. (2010) identified a heterozygous A382T mutation in affected
members of 3 unrelated Italian families with ALS10 with frontotemporal
dementia (612069). The mutation was not found in over 1,200 controls.
Affected individuals developed rapidly progressive muscle atrophy and
weakness associated with hyperreflexia, dysarthria, dysphagia, and
respiratory insufficiency between ages 25 and 78 years. Frontotemporal
dementia, characterized by disinhibition, emotional lability, apathy,
and executive dysfunction, developed soon after the onset of ALS. One
mutation carrier did not manifest neurologic symptoms at age 65 years.

Chio et al. (2011) identified the A382T mutation in 39 (28.7%) of 135
Sardinian patients with ALS, including 15 with familial disease and 24
with apparently sporadic disease. None of 156 ethnically matched
controls carried the mutation. Haplotype analysis of 5 patients with the
mutation identified a 94-SNP common risk haplotype spanning 663 kb
across the TARDBP locus on chromosome 1p36.22. The findings suggested a
founder effect in this population.

*FIELD* RF
1. Armakola, M.; Higgins, M. J.; Figley, M. D.; Barmada, S. J.; Scarborough,
E. A.; Diaz, Z.; Fang, X.; Shorter, J.; Krogan, N. J.; Finkbeiner,
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enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genet. 44:
1302-1309, 2012.

2. Ash, P. E. A.; Zhang, Y.-J.; Roberts, C. M.; Saldi, T.; Hutter,
H.; Buratti, E.; Petrucelli, L.; Link, C. D.: Neurotoxic effects
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2010.

3. Benajiba, L.; Le Ber, I.; Camuzat, A.; Lacoste, M.; Thomas-Anterion,
C.; Couratier, P.; Legallic, S.; Salachas, F.; Hannequin, D.; Decousus,
M.; Lacomblez, L.; Guedj, E.; Golfier, V.; Camu, W.; Dubois, B.; Campion,
D.; Meininger, V.; Brice, A.; French Clinical and Genetic Research
Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar
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4. Buratti, E.; Baralle, F. E.: Characterization and functional implications
of the RNA binding properties of nuclear factor TDP-43, a novel splicing
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5. Buratti, E.; Brindisi, A.; Pagani, F.; Baralle, F. E.: Nuclear
factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8
and causes skipping of exon 9: a functional link with disease penetrance.
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6. Buratti, E.; Dork, T.; Zucatto, E.; Pagani, R.; Romano, M.; Baralle,
F. E.: Nuclear factor TDP-43 and SR proteins promote in vitro and
in vivo CFTR exon 9 skipping. EMBO J. 20: 1774-1784, 2001.

7. Chio, A.; Borghero, G.; Pugliatti, M.; Ticca, A.; Calvo, A.; Moglia,
C.; Mutani, R.; Brunetti, M.; Ossola, I.; Marrosu, M. G.; Murru, M.
R.; Floris, G.; and 12 others: Large proportion of amyotrophic
lateral sclerosis cases in Sardinia due to a single founder mutation
of the TARDBP gene. Arch. Neurol. 68: 594-598, 2011.

8. Chio, A.; Calvo, A.; Moglia, C.; Restagno, G.; Ossola, I.; Brunetti,
M.; Montuschi, A.; Cistaro, A.; Ticca, A.; Traynor, B. J.; Schymick,
J. C.; Mutani, R.; Marrosu, M. G.; Murru, M. R.; Borghero, G.: Amyotrophic
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p.Ala382Thr TARDBP mutations. Arch. Neurol. 67: 1002-1009, 2010.

9. Corcia, P.; Valdmanis, P.; Millecamps, S.; Lionnet, C.; Blasco,
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10. Corrado, L.; Ratti, A.; Gellera, C.; Buratti, E.; Castellotti,
B.; Carlomagno, Y.; Ticozzi, N.; Mazzini, L.; Testa, L.; Taroni, F.;
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11. Elden, A. C.; Kim, H.-J.; Hart, M. P.; Chen-Plotkin, A. S.; Johnson,
B. S.; Fang, X.; Armakola, M.; Geser, F.; Greene, R.; Lu, M. M.; Padmanabhan,
A.; Clay-Falcone, D.; and 11 others: Ataxin-2 intermediate-length
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12. Gitcho, M. A.; Baloh, R. H.; Chakraverty, S.; Mayo, K.; Norton,
J. B.; Levitch, D.; Hatanpaa, K. J.; White, C. L., III.; Bigio, E.
H.; Caselli, R.; Baker, M.; Al-Lozi, M. T.; Morris, J. C.; Pestronk,
A.; Rademakers, R.; Goate, A. M.; Cairns, N. J.: TDP-43 A315T mutation
in familial motor neuron disease. Ann. Neurol. 63: 535-538, 2008.

13. Gitcho, M. A.; Bigio, E. H.; Mishra, M.; Johnson, N.; Weintraub,
S.; Mesulam, M.; Rademakers, R.; Chakraverty, S.; Cruchaga, C.; Morris,
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14. Groman, J. D.; Hefferon, T. W.; Casals, T.; Bassas, L.; Estivill,
X.; Georges, M. D.; Guittard, C.; Koudova, M.; Fallin, M. D.; Nemeth,
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15. Kabashi, E.; Daoud, H.; Riviere, J.-B.; Valdmanis, P. N.; Bourgouin,
P.; Provencher, P.; Pourcher, E.; Dion, P.; Dupre, N.; Rouleau, G.
A.: No TARDBP mutations in a French Canadian population of patients
with Parkinson disease. (Letter) Arch. Neurol. 66: 281-282, 2009.
Note: Erratum: Arch. Neurol. 66: 432 only, 2009.

16. Kabashi, E.; Lin, L.; Tradewell, M. L.; Dion, P. A.; Bercier,
V.; Bourgouin, P.; Rochefort, D.; Bel Hadj, S.; Durham, H. D.; Vande
Velde, C.; Rouleau, G. A.; Drapeau, P.: Gain and loss of function
of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in
vivo. Hum. Molec. Genet. 19: 671-683, 2010. Note: Erratum: Hum.
Molec. Genet. 19: 3102 only, 2010.

17. Kabashi, E.; Valdmanis, P. N.; Dion, P.; Spiegelman, D.; McConkey,
B. J.; Vande Velde, C.; Bouchard, J.-P.; Lacomblez, L.; Pochigaeva,
K.; Salachas, F.; Pradat, P.-F.; Camu, W.; Meininger, V.; Dupre, N.;
Rouleau, G. A.: TARDBP mutations in individuals with sporadic and
familial amyotrophic lateral sclerosis. Nature Genet. 40: 572-574,
2008.

18. Kovacs, G. G.; Murrell, J. R.; Horvath, S.; Haraszti, L.; Majtenyi,
K.; Molnar, M. J.; Budka, H.; Ghetti, B.; Spina, S.: TARDBP variation
associated with frontotemporal dementia, supranuclear gaze palsy,
and chorea. Mov. Disord. 24: 1843-1847, 2009.

19. Kuhnlein, P.; Sperfeld, A.-D.; Vanmassenhove, B.; Van Deerlin,
V.; Lee, V. M.-Y.; Trojanowski, J. Q.; Kretzschmar, H. A.; Ludolph,
A. C.; Neumann, M.: Two German kindreds with familial amyotrophic
lateral sclerosis due to TARDBP mutations. Arch. Neurol. 65: 1185-1189,
2008.

20. Lattante, S.; Rouleau, G. A.; Kabashi, E.: TARDBP and FUS mutations
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21. Luquin, N.; Yu, B.; Saunderson, R. B.; Trent, R. J.; Pamphlett,
R.: Genetic variants in the promoter of TARDBP in sporadic amyotrophic
lateral sclerosis. Neuromusc. Disord. 19: 696-700, 2009.

22. Mackenzie, I. R. A.; Bigio, E. H.; Ince, P. G.; Geser, F.; Neumann,
M.; Cairns, N. J.; Kwong, L. K.; Forman, M. S.; Ravits, J.; Stewart,
H.; Eisen, A.; McClusky, L.; Kretzschmar, H. A.; Monoranu, C. M.;
Highley, J. R.; Kirby, J.; Siddique, T.; Shaw, P. J.; Lee, V. M.-Y.;
Trojanowski, J. Q.: Pathological TDP-43 distinguishes sporadic amyotrophic
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23. 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.

24. Neumann, M.; Sampathu, D. M.; Kwong, L. K.; Truax, A. C.; Micsenyi,
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25. Ou, S.-H. I.; Wu, F.; Harrich, D.; Garcia-Martinez, L. F.; Gaynor,
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26. Sreedharan, J.; Blair, I. P.; Tripathi, V. B.; Hu, X.; Vance,
C.; Rogelj, B.; Ackerley, S.; Durnall, J. C.; Williams, K. L.; Buratti,
E.; Baralle, F.; de Belleroche, J.; Mitchell, J. D.; Leigh, P. N.;
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27. Tagawa, A.; Tan, C.-F.; Kikugawa, K.; Fukase, M.; Nakano, R.;
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28. Tsai, K.-J.; Yang, C.-H.; Fang, Y.-H.; Cho, K.-H.; Chien, W.-L.;
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29. Van Deerlin, V. M.; Leverenz, J. B.; Bekris, L. M.; Bird, T. D.;
Yuan, W.; Elman, L. B.; Clay, D.; Wood, E. M.; Chen-Plotkin, A. S.;
Martinez-Lage, M.; Steinbart, E.; McCluskey, L.; and 11 others:
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a genetic and histopathological analysis. Lancet Neurol. 7: 409-416,
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30. Wang, H.-Y.; Wang, I.-F.; Bose, J.; Shen, C.-K. J.: Structural
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31. Watanabe, S.; Kaneko, K.; Yamanaka, K.: Accelerated disease onset
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32. Wegorzewska, I.; Bell, S.; Cairns, N. J.; Miller, T. M.; Baloh,
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33. Wils, H.; Kleinberger, G.; Janssens, J.; Pereson, S.; Joris, G.;
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34. Yokoseki, A.; Shiga, A.; Tan, C.-F.; Tagawa, A.; Kaneko, H.; Koyama,
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*FIELD* CN
George E. Tiller - updated: 8/28/2013
Cassandra L. Kniffin - updated: 8/6/2013
Cassandra L. Kniffin - updated: 3/7/2013
Cassandra L. Kniffin - updated: 2/14/2013
Ada Hamosh - updated: 2/1/2013
Patricia A. Hartz - updated: 9/20/2012
Cassandra L. Kniffin - updated: 4/23/2012
Cassandra L. Kniffin - updated: 10/5/2011
George E. Tiller - updated: 2/8/2011
Paul J. Converse - updated: 2/7/2011
Cassandra L. Kniffin - updated: 1/14/2011
Cassandra L. Kniffin - updated: 9/28/2010
Ada Hamosh - updated: 9/14/2010
Cassandra L. Kniffin - updated: 10/27/2009
Cassandra L. Kniffin - updated: 7/14/2009
Cassandra L. Kniffin - updated: 3/27/2009
Cassandra L. Kniffin - updated: 3/18/2009
Carol A. Bocchini - updated: 11/7/2008
Cassandra L. Kniffin - updated: 10/8/2008
Victor A. McKusick - updated: 5/29/2008
Cassandra L. Kniffin - updated: 5/22/2008
Ada Hamosh - updated: 5/8/2008
Cassandra L. Kniffin - updated: 1/2/2008
Ada Hamosh - updated: 10/25/2006
Victor A. McKusick - updated: 5/28/2004
Patricia A. Hartz - updated: 2/6/2004

*FIELD* CD
Paul J. Converse: 6/26/2000

*FIELD* ED
carol: 09/16/2013
carol: 9/11/2013
tpirozzi: 8/30/2013
tpirozzi: 8/28/2013
carol: 8/9/2013
ckniffin: 8/6/2013
alopez: 3/13/2013
ckniffin: 3/7/2013
alopez: 2/20/2013
ckniffin: 2/14/2013
alopez: 2/7/2013
terry: 2/1/2013
mgross: 9/26/2012
terry: 9/20/2012
terry: 9/14/2012
terry: 7/27/2012
carol: 4/26/2012
ckniffin: 4/23/2012
carol: 10/13/2011
ckniffin: 10/5/2011
wwang: 5/18/2011
terry: 3/16/2011
wwang: 3/14/2011
terry: 2/8/2011
mgross: 2/8/2011
terry: 2/7/2011
wwang: 2/7/2011
ckniffin: 1/14/2011
ckniffin: 10/6/2010
wwang: 9/29/2010
ckniffin: 9/28/2010
alopez: 9/21/2010
terry: 9/14/2010
wwang: 11/16/2009
ckniffin: 10/27/2009
wwang: 7/31/2009
ckniffin: 7/14/2009
wwang: 3/31/2009
ckniffin: 3/27/2009
wwang: 3/26/2009
ckniffin: 3/18/2009
carol: 11/7/2008
wwang: 10/15/2008
ckniffin: 10/8/2008
alopez: 5/29/2008
ckniffin: 5/22/2008
alopez: 5/21/2008
terry: 5/8/2008
wwang: 1/22/2008
ckniffin: 1/2/2008
alopez: 11/2/2006
terry: 10/25/2006
alopez: 5/28/2004
mgross: 2/6/2004
mgross: 6/27/2000
mgross: 6/26/2000

MIM 612069
*RECORD*
*FIELD* NO
612069
*FIELD* TI
#612069 AMYOTROPHIC LATERAL SCLEROSIS 10, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA;
read moreALS10
FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED,
INCLUDED;;
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED;;
FTLD-TDP, TARDBP-RELATED, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because this form of autosomal
dominant amyotrophic lateral sclerosis, ALS10, is caused by heterozygous
mutation in the TARDBP gene (605078), which encodes the TDP43 protein,
on chromosome 1p36.

For a general phenotypic description and a discussion of genetic
heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).

Some patients with mutations in the TARDBP gene develop frontotemporal
dementia with TDP43-positive inclusions: see GRN-related FTLD-TDP
(607485) for a general phenotypic description of FTLD with TDP43
inclusions. Patients with TARDBP mutations and frontotemporal dementia
may or may not have associated signs of motor neuron disease.

CLINICAL FEATURES

Tagawa et al. (2007) described a Japanese family in which 4 members in 2
generations had adult onset of amyotrophic lateral sclerosis
characterized by relatively rapid progression of bulbar symptoms.
Autopsy of one of the patients showed neuropathology of the classic
form, with degenerative changes restricted to the upper and lower motor
neuron systems. In addition, Bunina bodies and ubiquitin-positive
skein-like inclusions were found in the remaining lower motor neurons,
and ubiquitin-positive intracytoplasmic inclusions were also found in
the putaminal small neurons. The authors noted that these findings were
typical of patients with sporadic ALS. Autosomal dominant inheritance
was proposed, but no mutations were identified in the SOD1 gene
(147450).

Sreedharan et al. (2008) described a Caucasian family of English descent
segregating autosomal dominant amyotrophic lateral sclerosis with
male-to-male transmission. Four of the affected individuals had definite
ALS by the El Escorial criteria, and another recently symptomatic
individual had probable ALS. Three had limb-onset ALS and 2 had
bulbar-onset ALS. The mean age of symptoms onset was 47 years (range 44
to 52). Mean disease duration was 5.5 years (range 4 to 7) from symptom
onset to death. The obligate carrier (who died aged 54 from severe
coronary atheroma) was reported by family members to have had gait
disturbance and declining upper limb strength consistent with ALS. There
was no history of dementia or any atypical features in the kindred.
Sreedharan et al. (2008) also reported a man who developed limb-onset
ALS at age 72 with a disease duration of 3 years, and in a man who
developed limb-onset ALS at age 65, with a disease duration of 5 years
and no atypical features.

Van Deerlin et al. (2008) reported a Caucasian father and daughter with
rapidly progressive ALS inherited in an autosomal dominant pattern. The
daughter presented with dysarthria and dysphagia at age 51 years and had
a rapidly progressive course involving the limbs and respiration. She
died after 13 months. Her father had presented with arm weakness at age
47 years and died after 16 months. Postmortem examination showed
findings consistent with ALS. Van Deerlin et al. (2008) also reported a
Chinese family in which 5 members spanning 2 generations had ALS with
onset between ages 41 and 60 years. Most showed rapid progression with
death within 1 or 2 years. Both spinal and bulbar onset were reported.
Postmortem examination of 2 patients showed changes consistent with ALS
as well as TDP43-positive inclusions in upper and lower motor neurons
and in various brain regions.

Kuhnlein et al. (2008) reported a German family with ALS10 confirmed by
genetic analysis (G348C; 605078.0007). The proband presented at age 55
years with paresis of the right hand, which progressed rapidly to
involve the arms and lower limbs and left her wheelchair-bound within
2.5 years. She died of respiratory insufficiency 3 years after disease
onset. The patient's mother had died of respiratory insufficiency due to
a similar disorder. There were no clinically relevant bulbar symptoms
and no cognitive impairment.

- Clinical Variability

Benajiba et al. (2009) reported a patient with onset of semantic
dementia at age 50 years. She later developed ritual behaviors, apathy,
social avoidance, aggressiveness, and bulimia, consistent with
frontotemporal dementia (see 600274). She also had bulbar symptoms of
ALS and upper and lower motor neuron disease in all 4 limbs. Her sister
had dysarthria and dysphagia at age 57, later developed upper and lower
limb motor neuron disease, and died at age 60. Their father reportedly
had motor neuron disease without dementia. An unrelated patient had
behavior disorders at age 52 consistent with frontotemporal dementia.
She developed bulbar symptoms at age 54, and later motor neuron disease
in the limbs. She died at age 58. All patients were found to carry the
same heterozygous mutation in the TARDBP gene (G295S; 605078.0010). The
findings expanded the phenotypic spectrum associated with mutations in
the TARDBP gene.

Kovacs et al. (2009) reported a Hungarian man who showed marked
personality changes beginning at age 35 years. This was followed by a
rapid deterioration in attention and thinking with psychomotor agitation
and insomnia, consistent with FTD. Neurologic examination showed
supranuclear gaze palsy, hyperkinetic choreiform movements, motor
stereotypies, and primitive reflexes. Motor neuron disease signs,
rigidity, and cerebellar ataxia were not present. Brain MRI showed
prominent atrophy of the mesencephalic tectum and caudate nuclei. He
died at age 37 years of pulmonary edema secondary to cardiac failure.
There was no family history of a similar disorder. Neuropathologic
examination showed moderate atrophy of the frontal lobes and caudate
nuclei, severe atrophy of tectum and tegmentum, and severe
depigmentation of the substantia nigra. Microscopic analysis showed mild
microvacuolar changes in the superficial cortical layers of the frontal
and cingulate gyri, and neuronal loss and astrogliosis in the
subcortical gray matter. Phospho-TDP43-immunoreactive deposits were
present in neuronal cytoplasmic inclusions in various brain regions,
including the cortex, basal ganglia, thalamus, and brainstem. Genetic
analysis excluded a pathologic HTT (613004) expansion and identified a
heterozygous mutation in the TARDBP gene (K263E; 605078.0011). The
findings indicated that TARDBP mutations can be associated with a wider
clinicopathologic spectrum of disorders than originally thought.

Gitcho et al. (2009) identified a heterozygous 2076G-A transition in the
3-prime untranslated region of the TARDBP gene (605078.0012) in affected
members of 2 unrelated families with either ALS10 with or without
frontotemporal dementia or isolated FTLD. The first family had 2
mutation carriers with a variable phenotype: the proband was a woman
with frontotemporal dementia without motor disease, whereas her brother
had lower motor neuron disease without dementia. The father and mother,
from whom DNA was not available, had ALS and lower motor neuron disease,
respectively, and it was not clear which parent likely transmitted the
TARDBP mutation. Neuropathologic analysis of the proband, who did not
have motor neuron disease, showed cortical atrophy, neuronal loss in the
hippocampus, hippocampal sclerosis, and TDP43-positive neuronal
cytoplasmic inclusions in the cortex and hippocampus. There was no
evidence of motor neuron loss from the motor nuclei of the brainstem.
The brother's neuropathologic findings were consistent with ALS and
showed TDP43-immunoreactivity in the anterior horn cells of the spinal
cord and neuronal cytoplasmic inclusions in the hippocampus. The second
family included a patient with familial ALS; no neuropathology was
available for that patient. These findings suggested that a common
molecular pathology can result in clinically heterogeneous phenotypes.

MOLECULAR GENETICS

Because TAR DNA-binding protein (TDP43) is the major protein in
ubiquitinated inclusions in ALS, Sreedharan et al. (2008) investigated
its role in the pathogenesis of the disorder. They screened 154 index
familial ALS cases for mutations in the TARDBP gene, which encodes
TDP43. Mutations in other genes associated with ALS had been excluded
from these cases. They identified a missense mutation in exon 6 of the
TARDBP gene in the index case from kindred ALS85, a Caucasian family of
English descent. The mutation was predicted to result in substitution of
valine for methionine at codon 337 (M337V; 605078.0001) and resides in a
strongly phylogenetically conserved region of TDP43. The mutation
segregated with disease and was present in 4 other affected individuals
in 3 branches and 2 generations of the extended kindred and was absent
from 9 unaffected sibs. Genomewide scan confirmed that linkage was
restricted to chromosome 1p36, to a region containing the TARDBP locus.
Sreedharan et al. (2008) sequenced all 6 exons of TARDBP in a cohort of
200 British sporadic ALS cases and identified another missense mutation
(Q331L; 605078.0002) in a man who developed limb-onset ALS at age 72
with a disease duration of 3 years. No mutation was detected in a screen
of all 6 exons from 500 British Caucasian controls. In a screen of
TARDBP in 2 further cohorts, 172 Australian Caucasian sporadic ALS
patients and 172 controls, as well as 200 British Caucasian controls,
Sreedharan et al. (2008) found a missense mutation (G294A; 605078.0003)
in a man who developed limb-onset ALS at age 65 with a disease duration
of 5 years and no atypical features.

In affected members of the Japanese family with ALS previously described
by Tagawa et al. (2007), Yokoseki et al. (2008) identified a
heterozygous mutation in the TARDBP gene (Q343R; 605078.0008).

In affected members of a European family with ALS10, Gitcho et al.
(2008) identified a heterozygous mutation in the TARDBP gene (A315T;
605078.0009).

Van Deerlin et al. (2008) identified heterozygous mutations in the
TARDBP gene (605078.0004; 605078.0005) in affected individuals of 2
unrelated families with autosomal dominant ALS10.

Kabashi et al. (2008) screened a panel of familial and sporadic ALS
cases for TARDBP mutations and found 8 missense mutations in 9
individuals. Protein lysates from individuals with ALS expressing TDP43
mutants showed accumulation of a smaller (approximately 28 kD) TDP43
protein product, mainly in a detergent-insoluble fraction.

Kuhnlein et al. (2008) identified mutations in the TARDBP gene in 2
(6.5%) of 31 probands with non-SOD1 familial ALS.

Millecamps et al. (2010) identified 6 different missense mutations in
the TARDBP gene in 7 (4.3%) of 162 French probands with familial ALS.
Three of the families had been previously reported. Patients with TARDBP
mutations had disease onset predominantly in the upper limb. One-third
of patients had rapid disease progression, two-thirds had a medium
disease course, and 1 had a slow disease course. There was evidence of
incomplete penetrance. One TARDBP mutation carrier developed
frontotemporal dementia 1 year after the onset of motor weakness.

Corrado et al. (2009) identified 12 different missense mutations in the
TARDBP gene (see, e.g., A382T; 605078.0013) in 18 of 666 Italian
probands with ALS. Six were familial, and 12 were apparently sporadic.
All patients had motor neuron disease, and none had dementia. All
mutations were located in exon 6 of the gene, and the most common
mutation was A382T, occurring in 7 patients. Haplotype analysis of A382T
carriers suggested a founder effect.

Chio et al. (2010) identified a heterozygous A382T mutation in affected
members of 3 unrelated Italian families with ALS10 with frontotemporal
dementia. Affected individuals developed rapidly progressive muscle
atrophy and weakness associated with hyperreflexia, dysarthria,
dysphagia, and respiratory insufficiency between ages 25 and 78 years.
Frontotemporal dementia, characterized by disinhibition, emotional
lability, apathy, and executive dysfunction, developed soon after the
onset of ALS. One mutation carrier did not manifest neurologic symptoms
at age 65 years.

GENOTYPE/PHENOTYPE CORRELATIONS

Corcia et al. (2012) identified 19 patients from 9 families with ALS10
and 9 patients with apparently sporadic ALS10. The patients were French,
and all carried mutations in the TARDBP gene. The mean age at onset was
53.4 years, and the upper limb was the most common site of onset. Only 2
patients had dementia. The median disease duration was 63 months; 2
patients were alive after 8 years. This group of patients was compared
to 3 cohorts: 737 patients with sporadic ALS; 192 patients with familial
ALS and no mutation in the SOD1 (147450), TARDPB (605078), or FUS
(137070) genes; and 58 patients with familial ALS due to SOD1 mutations.
In TARDBP-positive patients, onset was earlier (p = 0.0003), upper limb
onset was predominant (p = 0.002), and duration was longer (p = 0.0001)
than in patients with sporadic ALS. The mean age at onset was not
significantly different between TARDBP-positive and SOD1-positive
groups. TARDBP-positive and SOD1-positive groups had the longest
duration, but differed in site of onset: 60.7% upper limb onset for
TARDBP-positive and 74.1% lower limb onset for SOD1+ (p less than
0.0001). The TARDBP-positive patients were pooled with 117 ALS10
patients reported in the literature. Among all those with TARDBP
mutations, Caucasians tended to have upper limb onset, while Asians
tended to have bulbar onset. Among those with TARDBP mutations, G298S
(605078.0005) was associated with the shortest survival, whereas A315T
(605078.0009) and M337V (605078.0001) were associated with longest
duration.

POPULATION GENETICS

Corrado et al. (2009) noted that the frequency of TARDBP mutations is
not homogeneous among different populations. In particular, 26 of 39 ALS
patients carrying TARDBP mutations had an Italian or French origin,
suggesting higher frequency of TARDBP mutations in southern Europe
(average 3.4%; 8% in France and 2.7% in Italy) than in other Caucasian
populations (average 0.7%). After exclusion of the A382T (605078.0013)
mutation, which is likely to be a founder mutation, the frequency of
TARDBP mutations was still 3 times higher in southern European than in
northern European populations.

Chio et al. (2011) identified the A382T mutation in 39 (28.7%) of 135
Sardinian patients with ALS, including 15 with familial disease and 24
with apparently sporadic disease. None of 156 ethnically matched
controls carried the mutation. Haplotype analysis of 5 patients with the
mutation identified a 94-SNP common risk haplotype spanning 663 kb
across the TARDBP locus on chromosome 1p36.22. The findings suggested a
founder effect in this population.

ANIMAL MODEL

Wegorzewska et al. (2009) found that transgenic mice expressing a Tdp43
A315T mutation (605078.0009) developed progressive gait abnormalities at
about 3 to 4 months of age and died at about 5 months of age. Postmortem
examination showed accumulation of ubiquitinated proteins selectively in
the cytoplasm of neurons in cortical layer 5, including the motor
cortex. The inclusions did not stain for TDP43, but the changes were
associated with neuronal loss and increased glial reaction. Examination
of the spinal cord of mutant mice showed degeneration of descending
motor axons and ubiquitin pathology in large neurons of the ventral
horn; there was also loss of motor neurons. Mutant mice also showed
Tdp43 C-terminal fragments in the brain and spinal cord prior to the
onset of gait abnormalities. Wegorzewska et al. (2009) concluded that
since cytoplasmic Tdp43 aggregates were not present in mutant mice, they
are not required for neurodegeneration. These results indicated that the
selective neuronal vulnerability in Tdp43-related neurodegeneration is
related to altered DNA/RNA-binding protein function rather than to toxic
aggregation.

*FIELD* RF
1. Benajiba, L.; Le Ber, I.; Camuzat, A.; Lacoste, M.; Thomas-Anterion,
C.; Couratier, P.; Legallic, S.; Salachas, F.; Hannequin, D.; Decousus,
M.; Lacomblez, L.; Guedj, E.; Golfier, V.; Camu, W.; Dubois, B.; Campion,
D.; Meininger, V.; Brice, A.; French Clinical and Genetic Research
Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar
Degeneration with Motoneuron Disease: TARDBP mutations in motoneuron
disease with frontotemporal lobar degeneration. Ann. Neurol. 65:
470-474, 2009.

2. Chio, A.; Borghero, G.; Pugliatti, M.; Ticca, A.; Calvo, A.; Moglia,
C.; Mutani, R.; Brunetti, M.; Ossola, I.; Marrosu, M. G.; Murru, M.
R.; Floris, G.; and 12 others: Large proportion of amyotrophic
lateral sclerosis cases in Sardinia due to a single founder mutation
of the TARDBP gene. Arch. Neurol. 68: 594-598, 2011.

3. Chio, A.; Calvo, A.; Moglia, C.; Restagno, G.; Ossola, I.; Brunetti,
M.; Montuschi, A.; Cistaro, A.; Ticca, A.; Traynor, B. J.; Schymick,
J. C.; Mutani, R.; Marrosu, M. G.; Murru, M. R.; Borghero, G.: Amyotrophic
lateral sclerosis-frontotemporal lobar dementia in 3 families with
p.Ala382Thr TARDBP mutations. Arch. Neurol. 67: 1002-1009, 2010.

4. Corcia, P.; Valdmanis, P.; Millecamps, S.; Lionnet, C.; Blasco,
H.; Mouzat, K.; Daoud, H.; Belzil, V.; Morales, R.; Pageot, N.; Danel-Brunaud,
V.; Vandenberghe, N.; Pradat, P. F.; Couratier, P.; Salachas, F.;
Lumbroso, S.; Rouleau, G. A.; Meininger, V.; Camu, W.: Phenotype
and genotype analysis in amyotrophic lateral sclerosis with TARDBP
gene mutations. Neurology 78: 1519-1526, 2012.

5. Corrado, L.; Ratti, A.; Gellera, C.; Buratti, E.; Castellotti,
B.; Carlomagno, Y.; Ticozzi, N.; Mazzini, L.; Testa, L.; Taroni, F.;
Baralle, F. E.; Silani, V.; D'Alfonso, S.: High frequency of TARDBP
gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum.
Mutat. 30: 688-694, 2009.

6. Gitcho, M. A.; Baloh, R. H.; Chakraverty, S.; Mayo, K.; Norton,
J. B.; Levitch, D.; Hatanpaa, K. J.; White, C. L., III.; Bigio, E.
H.; Caselli, R.; Baker, M.; Al-Lozi, M. T.; Morris, J. C.; Pestronk,
A.; Rademakers, R.; Goate, A. M.; Cairns, N. J.: TDP-43 A315T mutation
in familial motor neuron disease. Ann. Neurol. 63: 535-538, 2008.

7. Gitcho, M. A.; Bigio, E. H.; Mishra, M.; Johnson, N.; Weintraub,
S.; Mesulam, M.; Rademakers, R.; Chakraverty, S.; Cruchaga, C.; Morris,
J. C.; Goate, A. M.; Cairns, N. J.: TARDBP 3-prime-UTR variant in
autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. Acta
Neuropath. 118: 633-645, 2009.

8. Kabashi, E.; Valdmanis, P. N.; Dion, P.; Spiegelman, D.; McConkey,
B. J.; Vande Velde, C.; Bouchard, J.-P.; Lacomblez, L.; Pochigaeva,
K.; Salachas, F.; Pradat, P.-F.; Camu, W.; Meininger, V.; Dupre, N.;
Rouleau, G. A.: TARDBP mutations in individuals with sporadic and
familial amyotrophic lateral sclerosis. Nature Genet. 40: 572-574,
2008.

9. Kovacs, G. G.; Murrell, J. R.; Horvath, S.; Haraszti, L.; Majtenyi,
K.; Molnar, M. J.; Budka, H.; Ghetti, B.; Spina, S.: TARDBP variation
associated with frontotemporal dementia, supranuclear gaze palsy,
and chorea. Mov. Disord. 24: 1843-1847, 2009.

10. Kuhnlein, P.; Sperfeld, A.-D.; Vanmassenhove, B.; Van Deerlin,
V.; Lee, V. M.-Y.; Trojanowski, J. Q.; Kretzschmar, H. A.; Ludolph,
A. C.; Neumann, M.: Two German kindreds with familial amyotrophic
lateral sclerosis due to TARDBP mutations. Arch. Neurol. 65: 1185-1189,
2008.

11. 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.

12. Sreedharan, J.; Blair, I. P.; Tripathi, V. B.; Hu, X.; Vance,
C.; Rogelj, B.; Ackerley, S.; Durnall, J. C.; Williams, K. L.; Buratti,
E.; Baralle, F.; de Belleroche, J.; Mitchell, J. D.; Leigh, P. N.;
Al-Chalabi, A.; Miller, C. C.; Nicholson, G.; Shaw, C. E.: TDP-43
mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:
1668-1672, 2008.

13. Tagawa, A.; Tan, C.-F.; Kikugawa, K.; Fukase, M.; Nakano, R.;
Onodera, O.; Nishizawa, M.; Takahashi, H.: Familial amyotrophic lateral
sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina
bodies and ubiquitin-positive skein-like inclusions in lower motor
neurons. Acta Neuropath. 113: 205-211, 2007.

14. Van Deerlin, V. M.; Leverenz, J. B.; Bekris, L. M.; Bird, T. D.;
Yuan, W.; Elman, L. B.; Clay, D.; Wood, E. M.; Chen-Plotkin, A. S.;
Martinez-Lage, M.; Steinbart, E.; McCluskey, L.; and 11 others:
TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology:
a genetic and histopathological analysis. Lancet Neurol. 7: 409-416,
2008.

15. Wegorzewska, I.; Bell, S.; Cairns, N. J.; Miller, T. M.; Baloh,
R. H.: TDP-43 mutant transgenic mice develop features of ALS and
frontotemporal lobar degeneration. Proc. Nat. Acad. Sci. 106: 18809-18814,
2009.

16. Yokoseki, A.; Shiga, A.; Tan, C.-F.; Tagawa, A.; Kaneko, H.; Koyama,
A.; Eguchi, H.; Tsujino, A.; Ikeuchi, T.; Kakita, A.; Okamoto, K.;
Nishizawa, M.; Takahashi, H.; Onodera, O.: TDP-43 mutation in familial
amyotrophic lateral sclerosis. Ann. Neurol. 63: 538-542, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Bulbar symptoms;
[Mouth];
Tongue hypotrophy

RESPIRATORY:
Respiratory insufficiency due to muscle weakness

ABDOMEN:
[Gastrointestinal];
Dysphagia

MUSCLE, SOFT TISSUE:
Muscle atrophy;
Muscle weakness;
Muscle biopsy shows chronic and active denervation

NEUROLOGIC:
[Central nervous system];
Upper and lower motor neuron disease;
Pyramidal signs;
Spasticity;
Hyperrflexia;
Extensor plantar responses;
Dysarthria;
Extrapyramidal symptoms may occur;
A subset of patients develop frontotemporal dementia;
[Behavioral/psychiatric manifestations];
Emotional lability;
Apathy;
Disinhibition;
Perseverative behavior

MISCELLANEOUS:
Variable age at onset (range 25 to 78 years);
Rapidly progressive

MOLECULAR BASIS:
Caused by mutation in the TAR DNA-binding protein (TARDBP, 605078.0001)

*FIELD* CD
Cassandra L. Kniffin: 1/14/2011

*FIELD* ED
joanna: 06/07/2012
ckniffin: 10/5/2011
ckniffin: 1/14/2011

*FIELD* CN
Cassandra L. Kniffin - updated: 3/7/2013
Cassandra L. Kniffin - updated: 4/23/2012
Cassandra L. Kniffin - updated: 10/5/2011
Cassandra L. Kniffin - updated: 1/14/2011
Cassandra L. Kniffin - updated: 9/28/2010
Cassandra L. Kniffin - updated: 7/14/2009
Cassandra L. Kniffin - updated: 3/27/2009
Carol A. Bocchini - updated: 11/7/2008
Cassandra L. Kniffin - updated: 10/8/2008
Victor A. McKusick - updated: 5/29/2008
Cassandra L. Kniffin - updated: 5/22/2008

*FIELD* CD
Ada Hamosh: 5/20/2008

*FIELD* ED
alopez: 03/13/2013
ckniffin: 3/7/2013
carol: 4/26/2012
ckniffin: 4/23/2012
carol: 10/13/2011
ckniffin: 10/5/2011
alopez: 9/22/2011
alopez: 9/21/2011
wwang: 5/18/2011
carol: 4/19/2011
terry: 3/16/2011
wwang: 3/14/2011
wwang: 2/7/2011
ckniffin: 1/14/2011
ckniffin: 10/6/2010
wwang: 9/29/2010
ckniffin: 9/28/2010
wwang: 7/31/2009
ckniffin: 7/14/2009
wwang: 3/31/2009
ckniffin: 3/27/2009
carol: 11/7/2008
wwang: 10/15/2008
ckniffin: 10/8/2008
alopez: 5/29/2008
ckniffin: 5/22/2008
alopez: 5/21/2008