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This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of\n                    <jats:italic>C9orf72<\/jats:italic>\n                    expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases. To further elucidate the mechanisms underlying\n                    <jats:italic>C9orf72<\/jats:italic>\n                    -related diseases and to identify potential disease modifiers, we performed an extensive RNA sequencing study. We included individuals for whom frontal cortex tissue was available: FTLD and FTLD\/MND patients with (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200934) or without (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200944) an expanded\n                    <jats:italic>C9orf72<\/jats:italic>\n                    repeat as well as control subjects (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924). In total, 6706 genes were differentially expressed between these groups (false discovery rate [FDR]\u2009&lt;\u20090.05). The top gene was\n                    <jats:italic>C9orf72<\/jats:italic>\n                    (FDR\u2009=\u20091.41E-14), which was roughly two-fold lower in\n                    <jats:italic>C9orf72<\/jats:italic>\n                    expansion carriers than in (disease) controls. Co-expression analysis revealed groups of correlated genes (modules) that were enriched for processes such as protein folding, RNA splicing, synaptic signaling, metabolism, and Golgi vesicle transport. Within our cohort of\n                    <jats:italic>C9orf72<\/jats:italic>\n                    expansion carriers, machine learning uncovered interesting candidates associated with clinico-pathological features, including age at onset (vascular endothelial growth factor A [\n                    <jats:italic>VEGFA<\/jats:italic>\n                    ]),\n                    <jats:italic>C9orf72<\/jats:italic>\n                    expansion size (cyclin dependent kinase like 1 [\n                    <jats:italic>CDKL1<\/jats:italic>\n                    ]), DPR protein levels (eukaryotic elongation factor 2 kinase [\n                    <jats:italic>EEF2K<\/jats:italic>\n                    ]), and survival after onset (small G protein signaling modulator 3 [\n                    <jats:italic>SGSM3<\/jats:italic>\n                    ]). Given the fact that we detected a module involved in vesicular transport in addition to a GTPase activator (\n                    <jats:italic>SGSM3<\/jats:italic>\n                    ) as a potential modifier, our findings seem to suggest that the presence of a\n                    <jats:italic>C9orf72<\/jats:italic>\n                    repeat expansion might hamper vesicular transport and that genes affecting this process may modify the phenotype of\n                    <jats:italic>C9orf72<\/jats:italic>\n                    -linked diseases.\n                  <\/jats:p>","DOI":"10.1186\/s40478-019-0797-0","type":"journal-article","created":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T04:03:12Z","timestamp":1570507392000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers"],"prefix":"10.1186","volume":"7","author":[{"given":"Dennis W.","family":"Dickson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmyne L.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariely","family":"DeJesus-Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"NiCole A.","family":"Finch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Pottier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania F.","family":"Gendron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxue","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neill R.","family":"Graff-Radford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley F.","family":"Boeve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C.","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Knopman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A.","family":"Josephs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Oskarsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Sheppard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan W.","family":"Asmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Rademakers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marka","family":"van Blitterswijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,8]]},"reference":[{"key":"797_CR1","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.jalz.2017.09.012","volume":"14","author":"M Allen","year":"2018","unstructured":"Allen M, Wang X, Burgess JD, Watzlawik J, Serie DJ, Younkin CS, Nguyen T, Malphrus KG, Lincoln S, Carrasquillo MM et al (2018) Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases. 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Research on autopsy samples is considered exempt from Human Subjects Research under Federal Regulation 45 CFR 46.101. All autopsies are obtained after consent by the legal next-of-kin or someone legally authorized to make this decision. Autopsies are performed with the explicit assumption that tissue will be used for both diagnostic evaluation and research.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MDJ and RR hold a patent on methods to screen for the hexanucleotide repeat expansion in the <i>C9orf72<\/i> gene. All other authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"150"}}