Mutations in PNKP cause microcephaly, seizures and defects in DNA repair

Jun Shen, Edward C Gilmore, Christine A Marshall, Mary Haddadin, John J Reynolds, Wafaa Eyaid, Adria Bodell, Brenda Barry, Danielle Gleason, Kathryn Allen, Vijay S Ganesh, Bernard S Chang, Arthur Grix, R Sean Hill, Meral Topcu, Keith W Caldecott, A James Barkovich, Christopher A Walsh

Research output: Contribution to journalArticlepeer-review


Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.

Original languageEnglish
Pages (from-to)245-9
Number of pages5
JournalNature Genetics
Issue number3
Early online date31 Jan 2010
Publication statusPublished - Mar 2010


  • Child
  • Chromosomes, Human, Pair 19
  • Consanguinity
  • DNA Repair/genetics
  • DNA Repair Enzymes/genetics
  • DNA Repair-Deficiency Disorders/complications
  • Developmental Disabilities/complications
  • Embryo, Mammalian
  • Family
  • Female
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Male
  • Microcephaly/complications
  • Mutation/physiology
  • Pedigree
  • Phosphotransferases (Alcohol Group Acceptor)/genetics
  • Polymorphism, Single Nucleotide
  • Seizures/complications


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