TY - JOUR
T1 - Cryptic Amyloidogenic Elements in the 3′ UTRs of Neurofilament Genes Trigger Axonal Neuropathy
AU - Rebelo, Adriana P.
AU - Abrams, Alexander J.
AU - Cottenie, Ellen
AU - Horga, Alejandro
AU - Gonzalez, Michael
AU - Bis, Dana M.
AU - Sanchez-Mejias, Avencia
AU - Pinto, Milena
AU - Buglo, Elena
AU - Markel, Kasey
AU - Prince, Jeffrey
AU - Laura, Matilde
AU - Houlden, Henry
AU - Blake, Julian
AU - Woodward, Cathy
AU - Sweeney, Mary G.
AU - Holton, Janice L.
AU - Hanna, Michael
AU - Dallman, Julia E.
AU - Auer-Grumbach, Michaela
AU - Reilly, Mary M.
AU - Zuchner, Stephan
N1 - Funding Information:
We deeply appreciate the commitment of the families who participated in this study. This work was supported by the NIH (R01NS075764, U54NS065712, and U54NS092091 to S.Z.), the Charcot-Marie-Tooth Association, the Austrian Science Fund (FWF P23223-B19 and P27634FW), and the Muscular Dystrophy Association. We also thank the Inherited Neuropathy Consortium for advice and general support. M.M.R. is grateful to the Medical Research Council (MRC Centre grant G0601943) and the National Institutes of Neurological Diseases and Stroke Office of Rare Diseases (U54NS065712) for their support. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres.
PY - 2016/4/7
Y1 - 2016/4/7
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2016.02.022
DO - 10.1016/j.ajhg.2016.02.022
M3 - Article
C2 - 27040688
AN - SCOPUS:84962050331
VL - 98
SP - 597
EP - 614
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -