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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.

Authors:
Michael P Holloway Bradley D DeNardo Chanika Phornphutkul Kevin Nguyen Colby Davis Cynthia Jackson Holly Richendrfer Robbert Creton Rachel A Altura

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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http://dx.doi.org/10.1038/npjgenmed.2016.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685301PMC
June 2016

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Enzymes 2020 28;48:277-319. Epub 2020 Sep 28.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States. Electronic address:

As an essential component of the translation machinery, aminoacyl-tRNA synthetases (aaRSs) are indispensable for cell viability. In complex multicellular organisms, this fundamental importance of aaRSs is further expanded by their broad regulatory functions, and reflected by their extensive human disease connections. This chapter focuses on the disease connection of the group of aaRSs supporting protein synthesis in the cytoplasm, including GlyRS and LysRS that are also used for mitochondrial translation. Read More

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J Emerg Med 2021 Apr 6. Epub 2021 Apr 6.

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J Clin Oncol 2021 Apr 9:JCO2002751. Epub 2021 Apr 9.

Biostatistics Division, Clinical Research Support Center, The University of Tokyo Hospital, Tokyo, Japan.

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J Clin Neurol 2021 Apr;17(2):322-324

Dizziness Center, Clinical Neuroscience Center, Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea.

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