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A third HSAN5 mutation disrupts the nerve growth factor furin cleavage site.

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cam.issuedOnline2018-10-08
dc.contributor.authorShaikh, Samiha S
dc.contributor.authorNahorski, Michael S
dc.contributor.authorWoods, C Geoffrey
dc.contributor.orcidShaikh, Samiha S [0000-0002-9757-6529]
dc.date.accessioned2018-11-23T00:32:53Z
dc.date.available2018-11-23T00:32:53Z
dc.date.issued2018
dc.description.abstractBi-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.
dc.description.sponsorshipSSS was funded by the UK Medical Research Council (MR/K017551/1), and MSN by the Wellcome Trust (200183/Z/15/Z).
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.33180
dc.identifier.eissn1744-8069
dc.identifier.issn1744-8069
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285836
dc.languageeng
dc.language.isoeng
dc.publisherSAGE Publications
dc.publisher.urlhttp://dx.doi.org/10.1177/1744806918809223
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHSAN5
dc.subjectNerve growth factor
dc.subjectfurin cleavage
dc.subjectmutation
dc.subjectAnimals
dc.subjectHereditary Sensory and Autonomic Neuropathies
dc.subjectMutation
dc.subjectNerve Growth Factor
dc.subjectNeurites
dc.subjectNeurons
dc.subjectPC12 Cells
dc.subjectPhosphorylation
dc.subjectProtein Precursors
dc.subjectRats
dc.titleA third HSAN5 mutation disrupts the nerve growth factor furin cleavage site.
dc.typeArticle
dcterms.dateAccepted2018-09-20
prism.publicationDate2018
prism.publicationNameMol Pain
prism.startingPage1744806918809223
prism.volume14
pubs.funder-project-idMRC (MR/K017551/1)
pubs.funder-project-idWellcome Trust (via University College London (UCL)) (532344)
rioxxterms.licenseref.startdate2018-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1177/1744806918809223

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