Publications by authors named "Colby Davis"

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An asymptomatic mutation complicating severe chemotherapy-induced peripheral neuropathy (CIPN): a case for personalised medicine and a zebrafish model of CIPN.

NPJ Genom Med 2016 8;1:16016. Epub 2016 Jun 8.

Department of Pediatrics, Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital and The Warren Alpert Medical School at Brown University, Providence, RI, USA.

Targeted next-generation sequencing (NGS) identified a novel loss of function mutation in , a gene linked to Charcot-Marie-Tooth disease (CMT), in a paediatric acute lymphoblastic leukaemia patient with severe chemotherapy-induced peripheral neuropathy (CIPN) due to vincristine. The patient was clinically asymptomatic, and lacked a family history of neuropathy. The effect of the mutation was modelled in a zebrafish knockdown system that recapitulated the symptoms of the patient both prior to and after treatment with vincristine. Confocal microscopy of pre- and post-synaptic markers revealed that the GARS knockdown results in changes to peripheral motor neurons, acetylcholine receptors and their co-localisation in neuromuscular junctions (NMJs), whereas a sensitive and reproducible stimulus-response assay demonstrated that the changes correlating with the GARS mutation in themselves fail to produce peripheral neuropathy symptoms. However, with vincristine treatment the GARS knockdown exacerbates decreased stimulus response and NMJ lesions. We propose that there is substantial benefit in the use of a targeted NGS screen of cancer patients who are to be treated with microtubule targeting agents for deleterious mutations in CMT linked genes, and for the screening in zebrafish of reagents that might inhibit CIPN.
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June 2016