The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25

Neurogenetics. 2018 Dec;19(4):215-225. doi: 10.1007/s10048-018-0555-7. Epub 2018 Jul 24.


Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.

Keywords: AOA4; CMT; CMT2B2; MED25; PNKP.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Substitution / genetics
  • Case-Control Studies
  • Charcot-Marie-Tooth Disease / genetics*
  • Consanguinity
  • Costa Rica
  • DNA Mutational Analysis
  • DNA Repair Enzymes / chemistry
  • DNA Repair Enzymes / genetics*
  • Family
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mediator Complex / genetics*
  • Middle Aged
  • Models, Molecular
  • Mutation, Missense
  • Pedigree
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Polymorphism, Single Nucleotide


  • MED25 protein, human
  • Mediator Complex
  • PNKP protein, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • DNA Repair Enzymes

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 2B2