title: Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy.
abstract: Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3' UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants.
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Adriana P
authors.initials: AP
authors.lastname: Rebelo
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Abrams
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: Cottenie
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Horga
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Bis
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Avencia
authors.initials: A
authors.lastname: Sanchez-Mejias
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Pinto
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Buglo
authors.affiliation: Department of Biology, University of Miami, Miami, FL 33146, USA.
authors.forename: Kasey
authors.initials: K
authors.lastname: Markel
authors.affiliation: Department of Biology, University of Miami, Miami, FL 33146, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Prince
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laura
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Woodward
authors.affiliation: Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Department of Biology, University of Miami, Miami, FL 33146, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Dallman
authors.affiliation: Department of Orthopaedics, Medical University Vienna, 1090 Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Molecular Neurosciences, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Electronic address: szuchner@med.miami.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D001369:Axons / Q000473:pathology*; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D016368:Frameshift Mutation; D006801:Humans; D007382:Intermediate Filaments / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D010375:Pedigree; D015027:Zebrafish / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions