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 S. Prince, Matilde Laura, Henry Houlden, Julian Blake, Cathy Woodward, Mary G. Sweeney, Janice L. Holton, Michael Hanna, Julia E. Dallman, Michaela Auer-GrumbachMary M. Reilly, Stephan Zuchner

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)597-614
Number of pages18
JournalAmerican journal of human genetics
Issue number4
StatePublished - Apr 7 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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