Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy

Andreas S. Beutler, Amit A. Kulkarni, Rahul Kanwar, Christopher J. Klein, Terry M. Therneau, Rui Qin, Michaela S. Banck, Ganesh K. Boora, Kathryn J. Ruddy, Yanhong Wu, Regenia L. Smalley, Julie M. Cunningham, Nguyet Anh Le-Lindqwister, Peter Beyerlein, Gary P. Schroth, Anthony J. Windebank, Stephan L Zuchner, Charles L. Loprinzi

Research output: Contribution to journalArticle

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Abstract

Objective: Mutations in Charcot-Marie-Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathy - considered "acquired" in medical parlance - is unknown. Chemotherapy-induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes.

Methods: A total of 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. Forty-nine CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood.

Results: A total of 119 (of 269) patients were identified from the 2 ends of the polyneuropathy phenotype distribution: patients that were most and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p=8 × 10-3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5 × 10-4). Three nonsynonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio=4.8, p=4 × 10-4).

Interpretation: The results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.

Original languageEnglish
Pages (from-to)727-737
Number of pages11
JournalAnnals of Neurology
Volume76
Issue number5
DOIs
StatePublished - Jan 1 2014

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Charcot-Marie-Tooth Disease
Polyneuropathies
Poisons
Peripheral Nervous System Diseases
Genes
Drug Therapy
Paclitaxel
Tooth Diseases
High-Throughput Nucleotide Sequencing
Neoplasms
Nucleotides
Odds Ratio
Clinical Trials
Phenotype
Mutation
DNA

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Beutler, A. S., Kulkarni, A. A., Kanwar, R., Klein, C. J., Therneau, T. M., Qin, R., ... Loprinzi, C. L. (2014). Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy. Annals of Neurology, 76(5), 727-737. https://doi.org/10.1002/ana.24265

Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy. / Beutler, Andreas S.; Kulkarni, Amit A.; Kanwar, Rahul; Klein, Christopher J.; Therneau, Terry M.; Qin, Rui; Banck, Michaela S.; Boora, Ganesh K.; Ruddy, Kathryn J.; Wu, Yanhong; Smalley, Regenia L.; Cunningham, Julie M.; Le-Lindqwister, Nguyet Anh; Beyerlein, Peter; Schroth, Gary P.; Windebank, Anthony J.; Zuchner, Stephan L; Loprinzi, Charles L.

In: Annals of Neurology, Vol. 76, No. 5, 01.01.2014, p. 727-737.

Research output: Contribution to journalArticle

Beutler, AS, Kulkarni, AA, Kanwar, R, Klein, CJ, Therneau, TM, Qin, R, Banck, MS, Boora, GK, Ruddy, KJ, Wu, Y, Smalley, RL, Cunningham, JM, Le-Lindqwister, NA, Beyerlein, P, Schroth, GP, Windebank, AJ, Zuchner, SL & Loprinzi, CL 2014, 'Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy', Annals of Neurology, vol. 76, no. 5, pp. 727-737. https://doi.org/10.1002/ana.24265
Beutler AS, Kulkarni AA, Kanwar R, Klein CJ, Therneau TM, Qin R et al. Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy. Annals of Neurology. 2014 Jan 1;76(5):727-737. https://doi.org/10.1002/ana.24265
Beutler, Andreas S. ; Kulkarni, Amit A. ; Kanwar, Rahul ; Klein, Christopher J. ; Therneau, Terry M. ; Qin, Rui ; Banck, Michaela S. ; Boora, Ganesh K. ; Ruddy, Kathryn J. ; Wu, Yanhong ; Smalley, Regenia L. ; Cunningham, Julie M. ; Le-Lindqwister, Nguyet Anh ; Beyerlein, Peter ; Schroth, Gary P. ; Windebank, Anthony J. ; Zuchner, Stephan L ; Loprinzi, Charles L. / Sequencing of charcot-marie-tooth disease genes in a toxic polyneuropathy. In: Annals of Neurology. 2014 ; Vol. 76, No. 5. pp. 727-737.
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AU - Klein, Christopher J.

AU - Therneau, Terry M.

AU - Qin, Rui

AU - Banck, Michaela S.

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AU - Ruddy, Kathryn J.

AU - Wu, Yanhong

AU - Smalley, Regenia L.

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N2 - Objective: Mutations in Charcot-Marie-Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathy - considered "acquired" in medical parlance - is unknown. Chemotherapy-induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes.Methods: A total of 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. Forty-nine CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood.Results: A total of 119 (of 269) patients were identified from the 2 ends of the polyneuropathy phenotype distribution: patients that were most and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p=8 × 10-3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5 × 10-4). Three nonsynonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio=4.8, p=4 × 10-4).Interpretation: The results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.

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