title: C9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.
abstract: A hexanucleotide (G4C2) repeat expansion in the 5' non-coding region C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Three modes of toxicity have been proposed: gain of function through formation of RNA foci and sequestration of RNA binding proteins; expression of dipeptide repeat proteins generated by repeat-associated non-ATG translation; and loss of function due to C9orf72 haploinsufficiency. Much is known about the proposed gain of function mechanisms, but there is little knowledge of the normal function of C9orf72 and the cellular consequences if its activity is perturbed. Here we will review what is known of C9orf72 at the transcript and protein levels and how changes in C9orf72 expression could contribute to disease pathogenesis. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.
authors.forename: Shangxi
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: MacNair
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.
authors.forename: Jesse
authors.initials: J
authors.lastname: McLean
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.
authors.forename: Phillip
authors.initials: P
authors.lastname: McGoldrick
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: McKeever
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.
authors.forename: Serena
authors.initials: S
authors.lastname: Soleimani
authors.affiliation: Sunnybrook Health Sciences Centre, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Keith
authors.affiliation: Sunnybrook Health Sciences Centre, Canada.
authors.forename: Lorne
authors.initials: L
authors.lastname: Zinman
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada. Electronic address: jan.robertson@utoronto.ca.
authors.forename: Janice
authors.initials: J
authors.lastname: Robertson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D020033:Protein Isoforms; D011506:Proteins
keywords: ALS/FTLD; C9-isoforms; C9-transcripts; C9orf72; Hexanucleotide repeat expansion