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Published on: January 7, 2019
Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy
Andreas S Beutler1, Amit A Kulkarni, Rahul Kanwar
1Department of Oncology, Mayo Clinic, Rochester, MN; Cancer Center, Mayo Clinic, Rochester, MN.
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.
Insights
Genetic variations in Charcot-Marie-Tooth disease genes are linked to chemotherapy-induced peripheral neuropathy (CIPN) susceptibility. This suggests genetic factors may influence acquired polyneuropathies.
Area of Science:
- Genetics
- Neurology
- Oncology
Background:
- Charcot-Marie-Tooth disease (CMT) is a rare inherited peripheral neuropathy.
- Chemotherapy-induced peripheral neuropathy (CIPN) is a common, unpredictable side effect of cancer treatment.
Purpose of the Study:
- To investigate if genetic variations in CMT genes are associated with susceptibility to CIPN.
- To use CIPN as a model for studying acquired polyneuropathies.
Main Methods:
- 269 neurologically asymptomatic cancer patients receiving paclitaxel were prospectively assessed for polyneuropathy.
- Targeted massively parallel sequencing of 49 CMT genes was performed on patient DNA.
Main Results:
- Patients most susceptible to paclitaxel-induced polyneuropathy had mutations in the CMT gene PRX.
- Genetic variations in the CMT gene ARHGEF10 were significantly associated with CIPN susceptibility.
- Specific variants in ARHGEF10, notably rs9657362, showed a strong association with CIPN.
Conclusions:
- Allelic variability in CMT genes is associated with susceptibility to CIPN.
- Acquired polyneuropathies may be influenced by genetic factors, including those related to known CMT genes.
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