PUBLICATION
Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy
- Authors
- Rebelo, A.P., Abrams, A.J., Cottenie, E., Horga, A., Gonzalez, M., Bis, D.M., Sanchez-Mejias, A., Pinto, M., Buglo, E., Markel, K., Prince, J., Laura, M., Houlden, H., Blake, J., Woodward, C., Sweeney, M.G., Holton, J.L., Hanna, M., Dallman, J.E., Auer-Grumbach, M., Reilly, M.M., Zuchner, S.
- ID
- ZDB-PUB-160405-4
- Date
- 2016
- Source
- American journal of human genetics 98(4): 597-614 (Journal)
- Registered Authors
- Dallman, Julia
- Keywords
- none
- MeSH Terms
-
- 3' Untranslated Regions/genetics*
- Amino Acid Sequence
- Amyotrophic Lateral Sclerosis/genetics
- Animals
- Axons/pathology*
- Cell Line
- Charcot-Marie-Tooth Disease/genetics
- Frameshift Mutation
- Humans
- Intermediate Filaments/genetics*
- Intermediate Filaments/metabolism
- Mice
- Molecular Sequence Data
- Motor Neurons/metabolism
- Motor Neurons/pathology*
- Mutation
- Pedigree
- Zebrafish/genetics
- PubMed
- 27040688 Full text @ Am. J. Hum. Genet.
Citation
Rebelo, A.P., Abrams, A.J., Cottenie, E., Horga, A., Gonzalez, M., Bis, D.M., Sanchez-Mejias, A., Pinto, M., Buglo, E., Markel, K., Prince, J., Laura, M., Houlden, H., Blake, J., Woodward, C., Sweeney, M.G., Holton, J.L., Hanna, M., Dallman, J.E., Auer-Grumbach, M., Reilly, M.M., Zuchner, S. (2016) Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy. American journal of human genetics. 98(4):597-614.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping