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Guanine nucleotide exchange C9orf72

 CI072_HUMAN             Reviewed;         481 AA.
Q96LT7; A8K5W0; D3DRK6; G8I0B6; Q6NUS9;
19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
19-JUL-2005, sequence version 2.
12-SEP-2018, entry version 125.
RecName: Full=Guanine nucleotide exchange C9orf72 {ECO:0000305};
Name=C9orf72;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA], INVOLVEMENT IN FTDALS1, SUBCELLULAR
LOCATION, AND TISSUE SPECIFICITY.
TISSUE=Frontal cortex;
PubMed=21944778; DOI=10.1016/j.neuron.2011.09.011;
Dejesus-Hernandez M., Mackenzie I.R., Boeve B.F., Boxer A.L.,
Baker M., Rutherford N.J., Nicholson A.M., Finch N.A., Flynn H.,
Adamson J., Kouri N., Wojtas A., Sengdy P., Hsiung G.Y., Karydas A.,
Seeley W.W., Josephs K.A., Coppola G., Geschwind D.H., Wszolek Z.K.,
Feldman H., Knopman D.S., Petersen R.C., Miller B.L., Dickson D.W.,
Boylan K.B., Graff-Radford N.R., Rademakers R.;
"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72
causes chromosome 9p-linked FTD and ALS.";
Neuron 72:245-256(2011).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
SEQUENCE [LARGE SCALE MRNA] OF 318-418 (ISOFORM 1).
TISSUE=Brain, and Cerebellum;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15164053; DOI=10.1038/nature02465;
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
Rogers J., Dunham I.;
"DNA sequence and analysis of human chromosome 9.";
Nature 429:369-374(2004).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Testis;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[6]
INVOLVEMENT IN FTDALS1, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
PubMed=21944779; DOI=10.1016/j.neuron.2011.09.010;
Renton A.E., Majounie E., Waite A., Simon-Sanchez J., Rollinson S.,
Gibbs J.R., Schymick J.C., Laaksovirta H., van Swieten J.C.,
Myllykangas L., Kalimo H., Paetau A., Abramzon Y., Remes A.M.,
Kaganovich A., Scholz S.W., Duckworth J., Ding J., Harmer D.W.,
Hernandez D.G., Johnson J.O., Mok K., Ryten M., Trabzuni D.,
Guerreiro R.J., Orrell R.W., Neal J., Murray A., Pearson J.,
Jansen I.E., Sondervan D., Seelaar H., Blake D., Young K.,
Halliwell N., Callister J.B., Toulson G., Richardson A., Gerhard A.,
Snowden J., Mann D., Neary D., Nalls M.A., Peuralinna T., Jansson L.,
Isoviita V.M., Kaivorinne A.L., Holtta-Vuori M., Ikonen E.,
Sulkava R., Benatar M., Wuu J., Chio A., Restagno G., Borghero G.,
Sabatelli M., Heckerman D., Rogaeva E., Zinman L., Rothstein J.D.,
Sendtner M., Drepper C., Eichler E.E., Alkan C., Abdullaev Z.,
Pack S.D., Dutra A., Pak E., Hardy J., Singleton A., Williams N.M.,
Heutink P., Pickering-Brown S., Morris H.R., Tienari P.J.,
Traynor B.J.;
"A hexanucleotide repeat expansion in C9orf72 is the cause of
chromosome 9p21-linked ALS-FTD.";
Neuron 72:257-268(2011).
[7]
INVOLVEMENT IN FTDALS1.
PubMed=22936364; DOI=10.1002/humu.22211;
Garcia-Redondo A., Dols-Icardo O., Rojas-Garcia R., Esteban-Perez J.,
Cordero-Vazquez P., Munoz-Blanco J.L., Catalina I., Gonzalez-Munoz M.,
Varona L., Sarasola E., Povedano M., Sevilla T., Guerrero A.,
Pardo J., de Munain A.L., Marquez-Infante C., de Rivera F.J.,
Pastor P., Jerico I., de Arcaya A.A., Mora J.S., Clarimon J.,
Gonzalo-Martinez J.F., Juarez-Rufian A., Atencia G.,
Jimenez-Bautista R., Moran Y., Mascias J., Hernandez-Barral M.,
Kapetanovic S., Garcia-Barcina M., Alcala C., Vela A.,
Ramirez-Ramos C., Galan L., Perez-Tur J., Quintans B., Sobrido M.J.,
Fernandez-Torron R., Poza J.J., Gorostidi A., Paradas C.,
Villoslada P., Larrode P., Capablo J.L., Pascual-Calvet J., Goni M.,
Morgado Y., Guitart M., Moreno-Laguna S., Rueda A.,
Martin-Estefania C., Cemillan C., Blesa R., Lleo A.;
"Analysis of the C9orf72 gene in patients with amyotrophic lateral
sclerosis in Spain and different populations worldwide.";
Hum. Mutat. 34:79-82(2013).
[8]
FUNCTION IN ENDOSOMAL TRAFFICKING, INTERACTION WITH RAB GTPASES;
HNRNPA1; HNRNPA2B1 AND UBQLN2, AND SUBCELLULAR LOCATION.
PubMed=24549040; DOI=10.1093/hmg/ddu068;
Farg M.A., Sundaramoorthy V., Sultana J.M., Yang S., Atkinson R.A.,
Levina V., Halloran M.A., Gleeson P.A., Blair I.P., Soo K.Y.,
King A.E., Atkin J.D.;
"C9ORF72, implicated in amytrophic lateral sclerosis and
frontotemporal dementia, regulates endosomal trafficking.";
Hum. Mol. Genet. 23:3579-3595(2014).
[9]
ERRATUM.
PubMed=28973528; DOI=10.1093/hmg/ddx309;
Farg M.A., Sundaramoorthy V., Sultana J.M., Yang S., Atkinson R.A.K.,
Levina V., Halloran M.A., Gleeson P.A., Blair I.P., Soo K.Y.,
King A.E., Atkin J.D.;
Hum. Mol. Genet. 26:4093-4094(2017).
[10]
PATHOLOGICAL MECHANISM.
PubMed=24598541; DOI=10.1038/nature13124;
Haeusler A.R., Donnelly C.J., Periz G., Simko E.A., Shaw P.G.,
Kim M.S., Maragakis N.J., Troncoso J.C., Pandey A., Sattler R.,
Rothstein J.D., Wang J.;
"C9orf72 nucleotide repeat structures initiate molecular cascades of
disease.";
Nature 507:195-200(2014).
[11]
DOMAIN ARCHITECTURE.
PubMed=23329412; DOI=10.1093/bioinformatics/bts725;
Levine T.P., Daniels R.D., Gatta A.T., Wong L.H., Hayes M.J.;
"The product of C9orf72, a gene strongly implicated in
neurodegeneration, is structurally related to DENN Rab-GEFs.";
Bioinformatics 29:499-503(2013).
[12]
SUBCELLULAR LOCATION (ISOFORMS 1 AND 2).
PubMed=26174152; DOI=10.1002/ana.24469;
Xiao S., MacNair L., McGoldrick P., McKeever P.M., McLean J.R.,
Zhang M., Keith J., Zinman L., Rogaeva E., Robertson J.;
"Isoform-specific antibodies reveal distinct subcellular localizations
of C9orf72 in amyotrophic lateral sclerosis.";
Ann. Neurol. 78:568-583(2015).
[13]
FUNCTION, IDENTIFICATION IN THE C9ORF72-SMCR8 COMPLEX, AND SUBCELLULAR
LOCATION.
PubMed=27193190; DOI=10.1186/s40478-016-0324-5;
Sullivan P.M., Zhou X., Robins A.M., Paushter D.H., Kim D.,
Smolka M.B., Hu F.;
"The ALS/FTLD associated protein C9orf72 associates with SMCR8 and
WDR41 to regulate the autophagy-lysosome pathway.";
Acta Neuropathol. Commun. 4:51-51(2016).
[14]
FUNCTION, AND IDENTIFICATION IN THE C9ORF72-SMCR8 COMPLEX.
PubMed=27103069; DOI=10.15252/embj.201593350;
Sellier C., Campanari M.L., Julie Corbier C., Gaucherot A.,
Kolb-Cheynel I., Oulad-Abdelghani M., Ruffenach F., Page A., Ciura S.,
Kabashi E., Charlet-Berguerand N.;
"Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2
to induce motor neuron dysfunction and cell death.";
EMBO J. 35:1276-1297(2016).
[15]
FUNCTION, AND INTERACTION WITH ATG13; RAB1A; RB1CC1 AND ULK1.
PubMed=27334615; DOI=10.15252/embj.201694401;
Webster C.P., Smith E.F., Bauer C.S., Moller A., Hautbergue G.M.,
Ferraiuolo L., Myszczynska M.A., Higginbottom A., Walsh M.J.,
Whitworth A.J., Kaspar B.K., Meyer K., Shaw P.J., Grierson A.J.,
De Vos K.J.;
"The C9orf72 protein interacts with Rab1a and the ULK1 complex to
regulate initiation of autophagy.";
EMBO J. 35:1656-1676(2016).
[16]
FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE C9ORF72-SMCR8
COMPLEX, AND INTERACTION WITH SMCR8.
PubMed=27559131; DOI=10.1091/mbc.E16-01-0003;
Amick J., Roczniak-Ferguson A., Ferguson S.M.;
"C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1
signaling.";
Mol. Biol. Cell 27:3040-3051(2016).
[17]
FUNCTION, INTERACTION WITH COFILIN, AND SUBCELLULAR LOCATION.
PubMed=27723745; DOI=10.1038/nn.4407;
Sivadasan R., Hornburg D., Drepper C., Frank N., Jablonka S.,
Hansel A., Lojewski X., Sterneckert J., Hermann A., Shaw P.J.,
Ince P.G., Mann M., Meissner F., Sendtner M.;
"C9ORF72 interaction with cofilin modulates actin dynamics in motor
neurons.";
Nat. Neurosci. 19:1610-1618(2016).
[18]
FUNCTION, IDENTIFICATION IN THE C9ORF72-SMCR8 COMPLEX, AND INTERACTION
WITH SMCR8.
PubMed=27617292; DOI=10.1126/sciadv.1601167;
Yang M., Liang C., Swaminathan K., Herrlinger S., Lai F.,
Shiekhattar R., Chen J.F.;
"A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual
role in autophagy.";
Sci. Adv. 2:E1601167-E1601167(2016).
[19]
FUNCTION, AND IDENTIFICATION IN THE C9ORF72-SMCR8 COMPLEX.
PubMed=28195531; DOI=10.7554/eLife.23063;
Jung J., Nayak A., Schaeffer V., Starzetz T., Kirsch A.K., Mueller S.,
Dikic I., Mittelbronn M., Behrends C.;
"Multiplex image-based autophagy RNAi screening identifies SMCR8 as
ULK1 kinase activity and gene expression regulator.";
Elife 6:0-0(2017).
[20]
FUNCTION (ISOFORMS 1 AND 2), AND SUBCELLULAR LOCATION.
PubMed=27037575; DOI=10.1007/s12035-016-9850-1;
Maharjan N., Kuenzli C., Buthey K., Saxena S.;
"C9ORF72 regulates stress granule formation and its deficiency impairs
stress granule assembly, hypersensitizing cells to stress.";
Mol. Neurobiol. 54:3062-3077(2017).
-!- FUNCTION: Component of the C9orf72-SMCR8 complex, a complex that
has guanine nucleotide exchange factor (GEF) activity and
regulates autophagy (PubMed:27193190, PubMed:27103069,
PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and
SMCR8 probably constitute the catalytic subunits that promote the
exchange of GDP to GTP, converting inactive GDP-bound RAB8A and
RAB39B into their active GTP-bound form, thereby promoting
autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8
complex also acts as a regulator of autophagy initiation by
interacting with the ATG1/ULK1 kinase complex and modulating its
protein kinase activity (PubMed:27617292). Positively regulates
initiation of autophagy by regulating the RAB1A-dependent
trafficking of the ATG1/ULK1 kinase complex to the phagophore
which leads to autophagosome formation (PubMed:27334615). Acts as
a regulator of mTORC1 signaling by promoting phosphorylation of
mTORC1 substrates (PubMed:27559131). Plays a role in endosomal
trafficking (PubMed:24549040). May be involved in regulating the
maturation of phagosomes to lysosomes (By similarity). Regulates
actin dynamics in motor neurons by inhibiting the GTP-binding
activity of ARF6, leading to ARF6 inactivation (PubMed:27723745).
This reduces the activity of the LIMK1 and LIMK2 kinases which are
responsible for phosphorylation and inactivation of cofilin,
leading to cofilin activation (PubMed:27723745). Positively
regulates axon extension and axon growth cone size in spinal motor
neurons (PubMed:27723745). Plays a role within the hematopoietic
system in restricting inflammation and the development of
autoimmunity (By similarity). {ECO:0000250|UniProtKB:Q6DFW0,
ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27103069,
ECO:0000269|PubMed:27193190, ECO:0000269|PubMed:27334615,
ECO:0000269|PubMed:27559131, ECO:0000269|PubMed:27617292,
ECO:0000269|PubMed:27723745, ECO:0000269|PubMed:28195531}.
-!- FUNCTION: Isoform 1: Regulates stress granule assembly in response
to cellular stress. {ECO:0000269|PubMed:27037575}.
-!- FUNCTION: Isoform 2: Does not play a role in regulation of stress
granule assembly in response to cellular stress.
{ECO:0000269|PubMed:27037575}.
-!- SUBUNIT: Interacts with SMCR8; the interaction is direct
(PubMed:27559131, PubMed:27617292). Component of the C9orf72-SMCR8
complex, at least composed of C9orf72, SMCR8 and WDR41
(PubMed:27193190, PubMed:27103069, PubMed:27559131,
PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex
associates with the ATG1/ULK1 kinase complex (PubMed:27617292,
PubMed:28195531). Interacts with ATG1/ULK1 kinase complex members
ULK1, ATG13 and RB1CC1 (PubMed:27334615). Interacts with HNRNPA1,
HNRNPA2B1 and UBQLN2 (PubMed:24549040). Interacts with small Rab
GTPase RAB1A; the interaction mediates recruitment of RAB1A to the
ATG1/ULK1 kinase complex (PubMed:27334615). Also interacts with
small Rab GTPase RAB7A (By similarity). Interacts with cofilin
(PubMed:27723745). Interacts with GTP-binding proteins ARF1 and
ARF6 (By similarity). {ECO:0000250|UniProtKB:Q6DFW0,
ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27103069,
ECO:0000269|PubMed:27193190, ECO:0000269|PubMed:27334615,
ECO:0000269|PubMed:27559131, ECO:0000269|PubMed:27617292,
ECO:0000269|PubMed:27723745, ECO:0000269|PubMed:28195531}.
-!- INTERACTION:
O43186:CRX; NbExp=3; IntAct=EBI-2961725, EBI-748171;
P49770:EIF2B2; NbExp=3; IntAct=EBI-2961725, EBI-718773;
Q53XC2:EIF2B2; NbExp=3; IntAct=EBI-2961725, EBI-10288660;
Q9BPX4:EIF2B2; NbExp=3; IntAct=EBI-2961725, EBI-10288788;
Q13287:NMI; NbExp=6; IntAct=EBI-2961725, EBI-372942;
Q04864:REL; NbExp=3; IntAct=EBI-2961725, EBI-307352;
Q8TEV9:SMCR8; NbExp=4; IntAct=EBI-2961725, EBI-2961718;
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21944779,
ECO:0000269|PubMed:27037575}. Cytoplasm
{ECO:0000269|PubMed:21944778, ECO:0000269|PubMed:27037575,
ECO:0000269|PubMed:27193190}. Cytoplasm, P-body
{ECO:0000269|PubMed:27037575}. Cytoplasm, Stress granule
{ECO:0000269|PubMed:27037575}. Endosome
{ECO:0000269|PubMed:24549040}. Lysosome
{ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27559131}.
Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:24549040}.
Secreted {ECO:0000269|PubMed:24549040}. Cell projection, axon
{ECO:0000269|PubMed:27723745}. Cell projection, growth cone
{ECO:0000269|PubMed:27723745}. Perikaryon
{ECO:0000250|UniProtKB:Q6DFW0}. Note=Detected in the cytoplasm of
neurons from brain tissue (PubMed:21944778). Detected in the
nucleus in fibroblasts (PubMed:21944779). During corticogenesis,
transitions from being predominantly cytoplasmic to a more even
nucleocytoplasmic distribution (By similarity).
{ECO:0000250|UniProtKB:Q6DFW0, ECO:0000269|PubMed:21944778,
ECO:0000269|PubMed:21944779, ECO:0000269|PubMed:27037575}.
-!- SUBCELLULAR LOCATION: Isoform 1: Perikaryon
{ECO:0000269|PubMed:26174152}. Cell projection, dendrite
{ECO:0000269|PubMed:26174152}. Note=Expressed diffusely throughout
the cytoplasm and dendritic processes of cerebellar Purkinje
cells. Also expressed diffusely throughout the cytoplasm of spinal
motor neurons. {ECO:0000269|PubMed:26174152}.
-!- SUBCELLULAR LOCATION: Isoform 2: Nucleus membrane
{ECO:0000269|PubMed:26174152}; Peripheral membrane protein
{ECO:0000305}. Nucleus {ECO:0000269|PubMed:26174152}.
Note=Detected at the nuclear membrane of cerebellar Purkinje cells
and spinal motor neurons. Also shows diffuse nuclear expression in
spinal motor neurons. {ECO:0000269|PubMed:26174152}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1; Synonyms=C9-L {ECO:0000303|PubMed:26174152}, C9(LF)
{ECO:0000303|PubMed:27037575};
IsoId=Q96LT7-1; Sequence=Displayed;
Note=Encoded by 2 transcripts differing in the 5' non-coding
region.;
Name=2; Synonyms=C9-S {ECO:0000303|PubMed:26174152}, C9(SF)
{ECO:0000303|PubMed:27037575};
IsoId=Q96LT7-2; Sequence=VSP_014745, VSP_014746;
-!- TISSUE SPECIFICITY: Both isoforms are widely expressed, including
kidney, lung, liver, heart, testis and several brain regions, such
as cerebellum. Also expressed in the frontal cortex and in
lymphoblasts (at protein level). {ECO:0000269|PubMed:21944778,
ECO:0000269|PubMed:21944779}.
-!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral
sclerosis 1 (FTDALS1) [MIM:105550]: An autosomal dominant
neurodegenerative disorder characterized by adult onset of
frontotemporal dementia and/or amyotrophic lateral sclerosis in an
affected individual. There is high intrafamilial variation.
Frontotemporal dementia is characterized by frontal and temporal
lobe atrophy associated with neuronal loss, gliosis, and dementia.
Patients exhibit progressive changes in social, behavioral, and/or
language function. Amyotrophic lateral sclerosis is characterized
by the death of motor neurons in the brain, brainstem, and spinal
cord, resulting in fatal paralysis. {ECO:0000269|PubMed:21944778,
ECO:0000269|PubMed:21944779, ECO:0000269|PubMed:22936364}.
Note=The disease is caused by mutations affecting the gene
represented in this entry. In the first intron of the gene, the
expansion of a GGGGCC hexanucleotide that can vary from 10 to
thousands of repeats, represents the most common genetic cause of
both familial and sporadic FTDALS. The hexanucleotide repeat
expansion (HRE) is structurally polymorphic and during
transcription, is responsible for the formation of RNA and DNA G-
quadruplexes resulting in the production of aborted transcripts at
the expense of functional transcripts. The accumulation of those
aborted transcripts may cause nucleolar stress and indirectly cell
death (PubMed:24598541). {ECO:0000269|PubMed:24598541}.
-----------------------------------------------------------------------
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Distributed under the Creative Commons Attribution (CC BY 4.0) License
-----------------------------------------------------------------------
EMBL; JN681271; AET41697.1; -; mRNA.
EMBL; AK057806; BAB71583.1; -; mRNA.
EMBL; AK291425; BAF84114.1; -; mRNA.
EMBL; AL451123; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CH471071; EAW58561.1; -; Genomic_DNA.
EMBL; CH471071; EAW58558.1; -; Genomic_DNA.
EMBL; CH471071; EAW58560.1; -; Genomic_DNA.
EMBL; BC068445; AAH68445.1; -; mRNA.
CCDS; CCDS6522.1; -. [Q96LT7-1]
CCDS; CCDS6523.1; -. [Q96LT7-2]
RefSeq; NP_001242983.1; NM_001256054.2. [Q96LT7-1]
RefSeq; NP_060795.1; NM_018325.4. [Q96LT7-1]
RefSeq; NP_659442.2; NM_145005.6. [Q96LT7-2]
UniGene; Hs.493639; -.
ProteinModelPortal; Q96LT7; -.
BioGrid; 128456; 11.
IntAct; Q96LT7; 22.
MINT; Q96LT7; -.
STRING; 9606.ENSP00000369339; -.
iPTMnet; Q96LT7; -.
PhosphoSitePlus; Q96LT7; -.
BioMuta; C9orf72; -.
DMDM; 71152412; -.
EPD; Q96LT7; -.
MaxQB; Q96LT7; -.
PaxDb; Q96LT7; -.
PeptideAtlas; Q96LT7; -.
PRIDE; Q96LT7; -.
ProteomicsDB; 77248; -.
ProteomicsDB; 77249; -. [Q96LT7-2]
DNASU; 203228; -.
Ensembl; ENST00000379995; ENSP00000369331; ENSG00000147894. [Q96LT7-2]
Ensembl; ENST00000379997; ENSP00000369333; ENSG00000147894. [Q96LT7-2]
Ensembl; ENST00000380003; ENSP00000369339; ENSG00000147894. [Q96LT7-1]
Ensembl; ENST00000619707; ENSP00000482753; ENSG00000147894. [Q96LT7-1]
GeneID; 203228; -.
KEGG; hsa:203228; -.
UCSC; uc003zqq.4; human. [Q96LT7-1]
CTD; 203228; -.
DisGeNET; 203228; -.
EuPathDB; HostDB:ENSG00000147894.14; -.
GeneCards; C9orf72; -.
GeneReviews; C9orf72; -.
HGNC; HGNC:28337; C9orf72.
HPA; HPA023873; -.
MalaCards; C9orf72; -.
MIM; 105550; phenotype.
MIM; 614260; gene.
neXtProt; NX_Q96LT7; -.
OpenTargets; ENSG00000147894; -.
Orphanet; 803; Amyotrophic lateral sclerosis.
Orphanet; 275864; Behavioral variant of frontotemporal dementia.
Orphanet; 275872; Frontotemporal dementia with motor neuron disease.
Orphanet; 401901; Huntington disease-like syndrome due to C9ORF72 expansions.
Orphanet; 100070; Progressive non-fluent aphasia.
Orphanet; 100069; Semantic dementia.
PharmGKB; PA134908144; -.
eggNOG; ENOG410IEBT; Eukaryota.
eggNOG; ENOG41117RW; LUCA.
GeneTree; ENSGT00390000005644; -.
HOGENOM; HOG000231721; -.
HOVERGEN; HBG060354; -.
InParanoid; Q96LT7; -.
OMA; VFQDVLH; -.
OrthoDB; EOG091G02YJ; -.
PhylomeDB; Q96LT7; -.
TreeFam; TF313315; -.
ChiTaRS; C9orf72; human.
GenomeRNAi; 203228; -.
PRO; PR:Q96LT7; -.
Proteomes; UP000005640; Chromosome 9.
Bgee; ENSG00000147894; Expressed in 196 organ(s), highest expression level in right lung.
CleanEx; HS_C9orf72; -.
Genevisible; Q96LT7; HS.
GO; GO:0005776; C:autophagosome; IDA:UniProtKB.
GO; GO:0044295; C:axonal growth cone; IDA:UniProtKB.
GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB.
GO; GO:0030425; C:dendrite; IDA:UniProtKB.
GO; GO:0005768; C:endosome; IDA:UniProtKB.
GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
GO; GO:0032045; C:guanyl-nucleotide exchange factor complex; IDA:HGNC.
GO; GO:0005764; C:lysosome; IDA:UniProtKB.
GO; GO:0044304; C:main axon; IDA:UniProtKB.
GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
GO; GO:0005634; C:nucleus; IDA:UniProtKB.
GO; GO:0000932; C:P-body; IDA:UniProtKB.
GO; GO:0043204; C:perikaryon; IDA:UniProtKB.
GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IEA:UniProtKB-KW.
GO; GO:0017137; F:Rab GTPase binding; IDA:UniProtKB.
GO; GO:0006914; P:autophagy; IMP:UniProtKB.
GO; GO:0048675; P:axon extension; IMP:UniProtKB.
GO; GO:0006897; P:endocytosis; IMP:UniProtKB.
GO; GO:1902774; P:late endosome to lysosome transport; ISS:UniProtKB.
GO; GO:1904425; P:negative regulation of GTP binding; IEA:Ensembl.
GO; GO:0001933; P:negative regulation of protein phosphorylation; IMP:UniProtKB.
GO; GO:0016239; P:positive regulation of macroautophagy; IMP:UniProtKB.
GO; GO:0110053; P:regulation of actin filament organization; IMP:UniProtKB.
GO; GO:2000785; P:regulation of autophagosome assembly; IMP:UniProtKB.
GO; GO:0010506; P:regulation of autophagy; IMP:UniProtKB.
GO; GO:1903432; P:regulation of TORC1 signaling; IMP:UniProtKB.
GO; GO:0034063; P:stress granule assembly; IMP:UniProtKB.
InterPro; IPR027819; C9orf72.
PANTHER; PTHR31855; PTHR31855; 1.
Pfam; PF15019; C9orf72-like; 1.
PROSITE; PS51835; DENN_C9ORF72; 1.
1: Evidence at protein level;
Alternative splicing; Amyotrophic lateral sclerosis; Autophagy;
Cell projection; Complete proteome; Cytoplasm; Cytoplasmic vesicle;
Endosome; Guanine-nucleotide releasing factor; Lysosome; Membrane;
Neurodegeneration; Nucleus; Polymorphism; Reference proteome;
Secreted.
CHAIN 1 481 Guanine nucleotide exchange C9orf72.
/FTId=PRO_0000089711.
DOMAIN 23 194 uDENN C9ORF72-type. {ECO:0000255|PROSITE-
ProRule:PRU01179}.
DOMAIN 200 343 cDENN C9ORF72-type. {ECO:0000255|PROSITE-
ProRule:PRU01179}.
DOMAIN 370 464 dDENN C9ORF72-type. {ECO:0000255|PROSITE-
ProRule:PRU01179}.
VAR_SEQ 222 222 N -> K (in isoform 2).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_014745.
VAR_SEQ 223 481 Missing (in isoform 2).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_014746.
VARIANT 207 207 N -> S (in dbSNP:rs17769294).
/FTId=VAR_050827.
SEQUENCE 481 AA; 54328 MW; B36C5576B3D268CE CRC64;
MSTLCPPPSP AVAKTEIALS GKSPLLAATF AYWDNILGPR VRHIWAPKTE QVLLSDGEIT
FLANHTLNGE ILRNAESGAI DVKFFVLSEK GVIIVSLIFD GNWNGDRSTY GLSIILPQTE
LSFYLPLHRV CVDRLTHIIR KGRIWMHKER QENVQKIILE GTERMEDQGQ SIIPMLTGEV
IPVMELLSSM KSHSVPEEID IADTVLNDDD IGDSCHEGFL LNAISSHLQT CGCSVVVGSS
AEKVNKIVRT LCLFLTPAER KCSRLCEAES SFKYESGLFV QGLLKDSTGS FVLPFRQVMY
APYPTTHIDV DVNTVKQMPP CHEHIYNQRR YMRSELTAFW RATSEEDMAQ DTIIYTDESF
TPDLNIFQDV LHRDTLVKAF LDQVFQLKPG LSLRSTFLAQ FLLVLHRKAL TLIKYIEDDT
QKGKKPFKSL RNLKIDLDLT AEGDLNIIMA LAEKIKPGLH SFIFGRPFYT SVQERDVLMT
F


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