title: Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy.
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)).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN; Cancer Center, Mayo Clinic, Rochester, MN.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Beutler
authors.forename: Amit A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanwar
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Klein
authors.forename: Terry M
authors.initials: TM
authors.lastname: Therneau
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Banck
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Boora
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Ruddy
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Regenia L
authors.initials: RL
authors.lastname: Smalley
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Nguyet Anh
authors.initials: NA
authors.lastname: Le-Lindqwister
authors.forename: Peter
authors.initials: P
authors.lastname: Beyerlein
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Windebank
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Charles L
authors.initials: CL
authors.lastname: Loprinzi
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000150:complications; D017239:Paclitaxel / Q000009:adverse effects; D011115:Polyneuropathies / Q000139:chemically induced* / Q000235:genetics*; D011446:Prospective Studies; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics
chemical_list: C577232:ARHGEF10 protein, human; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D064067:Rho Guanine Nucleotide Exchange Factors; D017239:Paclitaxel