Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy

Adriana P Rebelo; Alexander J Abrams; Ellen Cottenie; Alejandro Horga; Michael Gonzalez; Dana M Bis; Avencia Sanchez-Mejias; Milena Pinto; Elena Buglo; Kasey Markel; Jeffrey Prince; Matilde Laura; Henry Houlden; Julian Blake; Cathy Woodward; Mary G Sweeney; Janice L Holton; Michael Hanna; Julia E Dallman; Michaela Auer-Grumbach; Mary M Reilly; Stephan Zuchner

doi:10.1016/j.ajhg.2016.02.022

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Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy

Journal article

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Peer reviewed

Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy

Adriana P Rebelo, Alexander J Abrams, Ellen Cottenie, Alejandro Horga, Michael Gonzalez, Dana M Bis, Avencia Sanchez-Mejias, Milena Pinto, Elena Buglo, Kasey Markel, …

American journal of human genetics, Vol.98(4), pp.597-614

2016-04-07

DOI: https://doi.org/10.1016/j.ajhg.2016.02.022

PMCID: PMC4833435

PMID: 27040688

Abstract

Amino Acid Sequence

Cell Line

Intermediate Filaments - genetics

Frameshift Mutation

Amyotrophic Lateral Sclerosis - genetics

Humans

3' Untranslated Regions - genetics

Molecular Sequence Data

Intermediate Filaments - metabolism

Motor Neurons - pathology

Zebrafish - genetics

Charcot-Marie-Tooth Disease - genetics

Motor Neurons - metabolism

Animals

Pedigree

Axons - pathology

Mice

Mutation

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.253 Nerve Disorders; 1.253.1972 Charcot-Marie-Tooth Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy
Creators: Adriana P Rebelo - 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
Alexander J Abrams - 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
Ellen Cottenie - 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
Alejandro Horga - 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
Michael Gonzalez - 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
Dana M Bis - 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
Avencia Sanchez-Mejias - 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
Milena Pinto - 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
Elena Buglo - 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
Kasey Markel - Department of Biology, University of Miami, Miami, FL 33146, USA
Jeffrey Prince - Department of Biology, University of Miami, Miami, FL 33146, USA
Matilde Laura - 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
Henry Houlden - 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
Julian Blake - 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
Cathy Woodward - 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
Mary G Sweeney - Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Janice L Holton - 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
Michael Hanna - 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
Julia E Dallman - Department of Biology, University of Miami, Miami, FL 33146, USA
Michaela Auer-Grumbach - Department of Orthopaedics, Medical University Vienna, 1090 Vienna, Austria
Mary M Reilly - 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
Stephan Zuchner - 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
Publication Details: American journal of human genetics, Vol.98(4), pp.597-614
Publisher: United States
Grant note: G108/638 / Medical Research Council G0601943 / Medical Research Council MR/J004758/1 / Medical Research Council U54 NS092091 / NINDS NIH HHS U54NS065712 / NINDS NIH HHS P 27634 / Austrian Science Fund FWF R01NS075764 / NINDS NIH HHS G1001253 / Medical Research Council G0802760 / Medical Research Council U54NS09209 / NINDS NIH HHS U54 NS065712 / NINDS NIH HHS R01 NS075764 / NINDS NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; College of A&S; John P. Hussman Institute for Human Genomics; UMMG Department of Neurology; A&S - Biology
Language: English
Resource Type: Journal article
PMID: 27040688
PMCID: PMC4833435
Record Identifier: 991031558999002976