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Am J Hum Genet. 2016 Apr 7;98(4):597-614. doi: 10.1016/j.ajhg.2016.02.022. Epub 2016 Mar 31.

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

Author information

1
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.
2
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.
3
Department of Biology, University of Miami, Miami, FL 33146, USA.
4
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.
5
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.
6
Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
7
Department of Orthopaedics, Medical University Vienna, 1090 Vienna, Austria.
8
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.

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.

PMID:
27040688
PMCID:
PMC4833435
DOI:
10.1016/j.ajhg.2016.02.022
[Indexed for MEDLINE]
Free PMC Article

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