title: Retention of hexanucleotide repeat-containing intron in C9orf72 mRNA: implications for the pathogenesis of ALS/FTD.
abstract: BACKGROUND
  The most common forms of amyotrophic lateral sclerosis and frontotemporal dementia are caused by a large GGGGCC repeat expansion in the first intron of the C9orf72 gene. The repeat-containing intron should be degraded after being spliced out, however GGGGCC repeat-containing RNA species either accumulate in nuclear foci or are exported to the cytoplasm where they are translated into potentially toxic dipeptide repeat proteins by repeat-associated non-AUG-initiated (RAN) translation.
  
  
  RESULTS
  In order to determine the mechanisms of repeat-containing intron misprocessing, we have analyzed C9orf72 transcripts in lymphoblasts from C9orf72 expansion carriers (n = 15) and control individuals (n = 15). We have identified polyadenylated C9orf72 RNA species retaining the repeat-containing intron and in which downstream exons are spliced correctly resulting in a C9orf72 mRNA with an enlarged 5'-UTR containing the GGGGCC repeats. Intron-retaining transcripts are produced from both wild-type and mutant alleles. Intron-retaining C9orf72 transcripts were also detected in brain with a 2.7 fold increase measured in the frontal cortex from heterozygous expansion carriers (n = 11) compared to controls (n = 10). The level of intron-retaining transcripts was increased 5.9 fold in a case homozygous for the expansion. We also show that a large proportion of intron 1-retaining C9orf72 transcripts accumulate in the nucleus.
  
  
  CONCLUSIONS
  Retention of the repeat-containing intron in mature C9orf72 mRNA can potentially explain nuclear foci formation as well as nuclear export of GGGGCC repeat RNA and suggests that the misprocessing of C9orf72 transcripts initiates the pathogenic process caused by C9orf72 hexanucleotide repeat expansions as well as provides the basis for novel therapeutic strategies.
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Niblock
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Youn-Bok
authors.initials: YB
authors.lastname: Lee
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sardone
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Topp
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.|London Neurodegenerative Disease Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: London Neurodegenerative Disease Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Ludmer Building, 1033 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Ludmer Building, 1033 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Ludmer Building, 1033 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. jean-marc.gallo@kcl.ac.uk.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Gallo
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007438:Introns / Q000235:genetics; D008958:Models, Molecular; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D012333:RNA, Messenger