LOCUS       NM_018325               3231 bp    mRNA    linear   PRI 03-FEB-2025
DEFINITION  Homo sapiens C9orf72-SMCR8 complex subunit (C9orf72), transcript
            variant 2, mRNA.
ACCESSION   NM_018325
VERSION     NM_018325.5
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 3231)
  AUTHORS   Santos Silva,C., Gormicho,M., Simao,S., Pronto-Laborinho,A.C.,
            Alves,I., Pinto,S., Oliveira Santos,M. and de Carvalho,M.
  TITLE     C9orf72 gene repeat expansion phenotype profile of motor neurone
            disease in Portugal
  JOURNAL   J Neurol Sci 465, 123208 (2024)
   PUBMED   39226712
  REMARK    GeneRIF: C9orf72 gene repeat expansion phenotype profile of motor
            neurone disease in Portugal.
            Erratum:[J Neurol Sci. 2025 Jan 15;468:123363. doi:
            10.1016/j.jns.2024.123363.. PMID: 39705762]
REFERENCE   2  (bases 1 to 3231)
  AUTHORS   van der Geest,A.T., Jakobs,C.E., Ljubikj,T., Huffels,C.F.M.,
            Canizares Luna,M., Vieira de Sa,R., Adolfs,Y., de Wit,M.,
            Rutten,D.H., Kaal,M., Zwartkruis,M.M., Carcole,M., Groen,E.J.N.,
            Hol,E.M., Basak,O., Isaacs,A.M., Westeneng,H.J., van den Berg,L.H.,
            Veldink,J.H., Schlegel,D.K. and Pasterkamp,R.J.
  TITLE     Molecular pathology, developmental changes and synaptic dysfunction
            in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids
  JOURNAL   Acta Neuropathol Commun 12 (1), 152 (2024)
   PUBMED   39289761
  REMARK    GeneRIF: Molecular pathology, developmental changes and synaptic
            dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral
            organoids.
            Publication Status: Online-Only
REFERENCE   3  (bases 1 to 3231)
  AUTHORS   Longobardi,A., Bellini,S., Nicsanu,R., Pilotto,A., Geviti,A.,
            Facconi,A., Tolassi,C., Libri,I., Saraceno,C., Fostinelli,S.,
            Borroni,B., Padovani,A., Binetti,G. and Ghidoni,R.
  TITLE     Unveiling New Genetic Variants Associated with Age at Onset in
            Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to
            C9orf72 Repeat Expansions
  JOURNAL   Int J Mol Sci 25 (13), 7457 (2024)
   PUBMED   39000564
  REMARK    GeneRIF: Unveiling New Genetic Variants Associated with Age at
            Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration
            Due to C9orf72 Repeat Expansions.
            Publication Status: Online-Only
REFERENCE   4  (bases 1 to 3231)
  AUTHORS   Mori,K., Weng,S.M., Arzberger,T., May,S., Rentzsch,K., Kremmer,E.,
            Schmid,B., Kretzschmar,H.A., Cruts,M., Van Broeckhoven,C., Haass,C.
            and Edbauer,D.
  TITLE     The C9orf72 GGGGCC repeat is translated into aggregating
            dipeptide-repeat proteins in FTLD/ALS
  JOURNAL   Science 339 (6125), 1335-1338 (2013)
   PUBMED   23393093
  REMARK    GeneRIF: These findings directly link the FTLD/ALS-associated
            genetic mutation to the predominant pathology in patients with
            C9orf72 hexanucleotide expansion.
REFERENCE   5  (bases 1 to 3231)
  AUTHORS   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. and Traynor,B.J.
  CONSRTM   ITALSGEN Consortium
  TITLE     A hexanucleotide repeat expansion in C9ORF72 is the cause of
            chromosome 9p21-linked ALS-FTD
  JOURNAL   Neuron 72 (2), 257-268 (2011)
   PUBMED   21944779
  REMARK    GeneRIF: A hexanucleotide repeat expansion in C9ORF72 is the cause
            of chromosome 9p21-linked amyotrophic lateral
            sclerosis-frontotemporal dementia.
REFERENCE   6  (bases 1 to 3231)
  AUTHORS   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. and Rademakers,R.
  TITLE     Expanded GGGGCC hexanucleotide repeat in noncoding region of
            C9ORF72 causes chromosome 9p-linked FTD and ALS
  JOURNAL   Neuron 72 (2), 245-256 (2011)
   PUBMED   21944778
  REMARK    GeneRIF: Our findings indicate that repeat expansion in C9ORF72 is
            a major cause of both frontotemporal dementia and amyotrophic
            lateral sclerosis.
REFERENCE   7  (bases 1 to 3231)
  AUTHORS   Ostojic,J., Axelman,K., Lannfelt,L. and Froelich-Fabre,S.
  TITLE     No evidence of linkage to chromosome 9q21-22 in a Swedish family
            with frontotemporal dementia and amyotrophic lateral sclerosis
  JOURNAL   Neurosci Lett 340 (3), 245-247 (2003)
   PUBMED   12672552
REFERENCE   8  (bases 1 to 3231)
  AUTHORS   Hosler,B.A., Siddique,T., Sapp,P.C., Sailor,W., Huang,M.C.,
            Hossain,A., Daube,J.R., Nance,M., Fan,C., Kaplan,J., Hung,W.Y.,
            McKenna-Yasek,D., Haines,J.L., Pericak-Vance,M.A., Horvitz,H.R. and
            Brown,R.H. Jr.
  TITLE     Linkage of familial amyotrophic lateral sclerosis with
            frontotemporal dementia to chromosome 9q21-q22
  JOURNAL   JAMA 284 (13), 1664-1669 (2000)
   PUBMED   11015796
REFERENCE   9  (bases 1 to 3231)
  AUTHORS   Gossye,H., Engelborghs,S., Van Broeckhoven,C. and van der Zee,J.
  TITLE     C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral
            Sclerosis
  JOURNAL   (in) Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE and
            Amemiya A (Eds.);
            GENEREVIEWS(R);
            (1993)
   PUBMED   25577942
REFERENCE   10 (bases 1 to 3231)
  AUTHORS   Siddique,N. and Siddique,T.
  TITLE     Amyotrophic Lateral Sclerosis Overview
  JOURNAL   (in) Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE and
            Amemiya A (Eds.);
            GENEREVIEWS(R);
            (1993)
   PUBMED   20301623
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from AK291425.1, BC068445.1,
            BC020851.2, BC039112.1, BQ777139.1 and AL832229.1.
            This sequence is a reference standard in the RefSeqGene project.
            
            On Jun 28, 2019 this sequence version replaced NM_018325.4.
            
            Summary: The protein encoded by this gene plays an important role
            in the regulation of endosomal trafficking, and has been shown to
            interact with Rab proteins that are involved in autophagy and
            endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies
            to 700-1600 copies in the intronic sequence between alternate 5'
            exons in transcripts from this gene is associated with 9p-linked
            ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal
            dementia) (PMID: 21944778, 21944779). Studies suggest that
            hexanucleotide expansions could result in the selective
            stabilization of repeat-containing pre-mRNA, and the accumulation
            of insoluble dipeptide repeat protein aggregates that could be
            pathogenic in FTD-ALS patients (PMID: 23393093). Alternative
            splicing results in multiple transcript variants encoding different
            isoforms. [provided by RefSeq, Jul 2016].
            
            Transcript Variant: This variant (2) differs in the 5' UTR compared
            to variant 3. Both variants 2 and 3 encode the same protein.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: AL832229.1, BC068445.1 [ECO:0000332]
            RNAseq introns              :: mixed sample support SAMEA1965299,
                                           SAMEA1966682 [ECO:0006172]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match     :: ENST00000380003.8/ ENSP00000369339.3
            RefSeq Select criteria :: based on manual assertion, conservation,
                                      expression, longest protein
            ##RefSeq-Attributes-END##
            COMPLETENESS: complete on the 3' end.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-39                AK291425.1         3-41
            40-68               BC068445.1         1-29
            69-602              BC020851.2         18-551
            603-2795            BC068445.1         564-2756
            2796-2884           BC039112.1         903-991
            2885-3087           BQ777139.1         424-626
            3088-3231           AL832229.1         3057-3200
FEATURES             Location/Qualifiers
     source          1..3231
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="9"
                     /map="9p21.2"
     gene            1..3231
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /note="C9orf72-SMCR8 complex subunit"
                     /db_xref="GeneID:203228"
                     /db_xref="HGNC:HGNC:28337"
                     /db_xref="MIM:614260"
     exon            1..51
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            52..539
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     CDS             96..1541
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /note="isoform a is encoded by transcript variant 2;
                     protein C9orf72; guanine nucleotide exchange C9orf72;
                     guanine nucleotide exchange factor C9orf72"
                     /codon_start=1
                     /product="guanine nucleotide exchange factor C9orf72
                     isoform a"
                     /protein_id="NP_060795.1"
                     /db_xref="CCDS:CCDS6522.1"
                     /db_xref="GeneID:203228"
                     /db_xref="HGNC:HGNC:28337"
                     /db_xref="MIM:614260"
                     /translation="MSTLCPPPSPAVAKTEIALSGKSPLLAATFAYWDNILGPRVRHI
                     WAPKTEQVLLSDGEITFLANHTLNGEILRNAESGAIDVKFFVLSEKGVIIVSLIFDGN
                     WNGDRSTYGLSIILPQTELSFYLPLHRVCVDRLTHIIRKGRIWMHKERQENVQKIILE
                     GTERMEDQGQSIIPMLTGEVIPVMELLSSMKSHSVPEEIDIADTVLNDDDIGDSCHEG
                     FLLNAISSHLQTCGCSVVVGSSAEKVNKIVRTLCLFLTPAERKCSRLCEAESSFKYES
                     GLFVQGLLKDSTGSFVLPFRQVMYAPYPTTHIDVDVNTVKQMPPCHEHIYNQRRYMRS
                     ELTAFWRATSEEDMAQDTIIYTDESFTPDLNIFQDVLHRDTLVKAFLDQVFQLKPGLS
                     LRSTFLAQFLLVLHRKALTLIKYIEDDTQKGKKPFKSLRNLKIDLDLTAEGDLNIIMA
                     LAEKIKPGLHSFIFGRPFYTSVQERDVLMTF"
     exon            540..599
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            600..695
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            696..760
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            761..833
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            834..950
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            951..1186
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            1187..1244
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            1245..1354
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     exon            1355..3231
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /inference="alignment:Splign:2.1.0"
     regulatory      3210..3215
                     /regulatory_class="polyA_signal_sequence"
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /note="hexamer: AATAAA"
     polyA_site      3231
                     /gene="C9orf72"
                     /gene_synonym="ALSFTD; DENND9; DENNL72; FTDALS; FTDALS1"
                     /note="major polyA site"
ORIGIN      
        1 ggttgcggtg cctgcgcccg cggcggcgga ggcgcaggcg gtggcgagtg gatatctccg
       61 gagcatttgg ataatgtgac agttggaatg cagtgatgtc gactctttgc ccaccgccat
      121 ctccagctgt tgccaagaca gagattgctt taagtggcaa atcaccttta ttagcagcta
      181 cttttgctta ctgggacaat attcttggtc ctagagtaag gcacatttgg gctccaaaga
      241 cagaacaggt acttctcagt gatggagaaa taacttttct tgccaaccac actctaaatg
      301 gagaaatcct tcgaaatgca gagagtggtg ctatagatgt aaagtttttt gtcttgtctg
      361 aaaagggagt gattattgtt tcattaatct ttgatggaaa ctggaatggg gatcgcagca
      421 catatggact atcaattata cttccacaga cagaacttag tttctacctc ccacttcata
      481 gagtgtgtgt tgatagatta acacatataa tccggaaagg aagaatatgg atgcataagg
      541 aaagacaaga aaatgtccag aagattatct tagaaggcac agagagaatg gaagatcagg
      601 gtcagagtat tattccaatg cttactggag aagtgattcc tgtaatggaa ctgctttcat
      661 ctatgaaatc acacagtgtt cctgaagaaa tagatatagc tgatacagta ctcaatgatg
      721 atgatattgg tgacagctgt catgaaggct ttcttctcaa tgccatcagc tcacacttgc
      781 aaacctgtgg ctgttccgtt gtagtaggta gcagtgcaga gaaagtaaat aagatagtca
      841 gaacattatg cctttttctg actccagcag agagaaaatg ctccaggtta tgtgaagcag
      901 aatcatcatt taaatatgag tcagggctct ttgtacaagg cctgctaaag gattcaactg
      961 gaagctttgt gctgcctttc cggcaagtca tgtatgctcc atatcccacc acacacatag
     1021 atgtggatgt caatactgtg aagcagatgc caccctgtca tgaacatatt tataatcagc
     1081 gtagatacat gagatccgag ctgacagcct tctggagagc cacttcagaa gaagacatgg
     1141 ctcaggatac gatcatctac actgacgaaa gctttactcc tgatttgaat atttttcaag
     1201 atgtcttaca cagagacact ctagtgaaag ccttcctgga tcaggtcttt cagctgaaac
     1261 ctggcttatc tctcagaagt actttccttg cacagtttct acttgtcctt cacagaaaag
     1321 ccttgacact aataaaatat atagaagacg atacgcagaa gggaaaaaag ccctttaaat
     1381 ctcttcggaa cctgaagata gaccttgatt taacagcaga gggcgatctt aacataataa
     1441 tggctctggc tgagaaaatt aaaccaggcc tacactcttt tatctttgga agacctttct
     1501 acactagtgt gcaagaacga gatgttctaa tgacttttta aatgtgtaac ttaataagcc
     1561 tattccatca caatcatgat cgctggtaaa gtagctcagt ggtgtgggga aacgttcccc
     1621 tggatcatac tccagaattc tgctctcagc aattgcagtt aagtaagtta cactacagtt
     1681 ctcacaagag cctgtgaggg gatgtcaggt gcatcattac attgggtgtc tcttttccta
     1741 gatttatgct tttgggatac agacctatgt ttacaatata ataaatatta ttgctatctt
     1801 ttaaagatat aataatagga tgtaaacttg accacaacta ctgttttttt gaaatacatg
     1861 attcatggtt tacatgtgtc aaggtgaaat ctgagttggc ttttacagat agttgacttt
     1921 ctatcttttg gcattctttg gtgtgtagaa ttactgtaat acttctgcaa tcaactgaaa
     1981 actagagcct ttaaatgatt tcaattccac agaaagaaag tgagcttgaa cataggatga
     2041 gctttagaaa gaaaattgat caagcagatg tttaattgga attgattatt agatcctact
     2101 ttgtggattt agtccctggg attcagtctg tagaaatgtc taatagttct ctatagtcct
     2161 tgttcctggt gaaccacagt tagggtgttt tgtttatttt attgttcttg ctattgttga
     2221 tattctatgt agttgagctc tgtaaaagga aattgtattt tatgttttag taattgttgc
     2281 caacttttta aattaatttt cattattttt gagccaaatt gaaatgtgca cctcctgtgc
     2341 cttttttctc cttagaaaat ctaattactt ggaacaagtt cagatttcac tggtcagtca
     2401 ttttcatctt gttttcttct tgctaagtct taccatgtac ctgctttggc aatcattgca
     2461 actctgagat tataaaatgc cttagagaat atactaacta ataagatctt tttttcagaa
     2521 acagaaaata gttccttgag tacttccttc ttgcatttct gcctatgttt ttgaagttgt
     2581 tgctgtttgc ctgcaatagg ctataaggaa tagcaggaga aattttactg aagtgctgtt
     2641 ttcctaggtg ctactttggc agagctaagt tatcttttgt tttcttaatg cgtttggacc
     2701 attttgctgg ctataaaata actgattaat ataattctaa cacaatgttg acattgtagt
     2761 tacacaaaca caaataaata ttttatttaa aattctggaa gtaatataaa agggaaaata
     2821 tatttataag aaagggataa aggtaataga gcccttctgc cccccaccca ccaaatttac
     2881 acaacaaaat gacatgttcg aatgtgaaag gtcataatag ctttcccatc atgaatcaga
     2941 aagatgtgga cagcttgatg ttttagacaa ccactgaact agatgactgt tgtactgtag
     3001 ctcagtcatt taaaaaatat ataaatacta ccttgtagtg tcccatactg tgttttttac
     3061 atggtagatt cttatttaag tgctaactgg ttattttctt tggctggttt attgtactgt
     3121 tatacagaat gtaagttgta cagtgaaata agttattaaa gcatgtgtaa acattgttat
     3181 atatcttttc tcctaaatgg agaattttga ataaaatata tttgaaattt t
//
