A third HSAN5 mutation disrupts the nerve growth factor furin cleavage site.
Nahorski, Michael S
Woods, C Geoffrey
MetadataShow full item record
Shaikh, S. S., Nahorski, M. S., & Woods, C. G. (2018). A third HSAN5 mutation disrupts the nerve growth factor furin cleavage site.. Mol Pain, 14 1744806918809223. https://doi.org/10.1177/1744806918809223
Bi-allelic dysfunctional mutations in nerve growth factor (NGF) cause the rare human phenotype hereditary sensory and autonomic neuropathy type 5 (HSAN5). We describe a novel NGF mutation in an individual with typical HSAN5 findings. The mutation c.361C>T, p.R121W is at the last residue of the furin cleavage motif Arg-Ser-Lys-Arg in proNGF. We show that the p.R121W mutation completely abolishes the formation of mature NGF-β. Surprisingly, mutant p.R121W cells produced very little proNGF. Instead, the two progressive cleavage products of proNGF were produced, proA-NGF and proB-NGF, with proB-NGF being the predominant NGF-derived peptide and the only peptide secreted by mutant p.R121W cells. We found that the ability of the p.R121W mutation to cause tropomyosin receptor kinase A autophosphorylation and mitogen-activated protein kinase phosphorylation was significantly reduced compared to controls (p < 0.05 and p < 0.01). By studying the PC12 cell line morphology and neurite length over a week, we found the p.R121W mutation had residual, but much reduced, neurotrophic activity when compared to wild-type NGF. Finally, we assessed whether the p.R121W mutation affected apoptosis and found a reduced protective effect compared to wild-type NGF. Our results suggest that the p.R121W NGF mutation causes HSAN5 through negating the ability of furin to cleave proNGF to produce NGF-β.
HSAN5, Nerve growth factor, furin cleavage, mutation, Animals, Hereditary Sensory and Autonomic Neuropathies, Mutation, Nerve Growth Factor, Neurites, Neurons, PC12 Cells, Phosphorylation, Protein Precursors, Rats
SSS was funded by the UK Medical Research Council (MR/K017551/1), and MSN by the Wellcome Trust (200183/Z/15/Z).
Wellcome Trust (via University College London (UCL)) (532344)
External DOI: https://doi.org/10.1177/1744806918809223
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285836
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: firstname.lastname@example.org