Hypomorphic PCNA mutation underlies a human DNA repair disorder

J Clin Invest. 2014 Jul;124(7):3137-46. doi: 10.1172/JCI74593. Epub 2014 Jun 9.


Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Together, our findings detail a mutation of PCNA in humans associated with a neurodegenerative phenotype, displaying clinical and molecular features common to other DNA repair disorders, which we showed to be attributable to a hypomorphic amino acid alteration.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aging, Premature / genetics
  • Amino Acid Substitution
  • Child
  • Chromosomes, Human, Pair 20 / genetics
  • DNA Mutational Analysis
  • DNA Repair-Deficiency Disorders / genetics*
  • DNA Repair-Deficiency Disorders / pathology
  • DNA Repair-Deficiency Disorders / physiopathology
  • Dwarfism / genetics
  • Female
  • Hearing Loss / genetics
  • Homozygote
  • Humans
  • Male
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics*
  • Mutant Proteins / metabolism
  • Mutation, Missense*
  • Nerve Degeneration / genetics
  • Pedigree
  • Phenotype
  • Photosensitivity Disorders / genetics
  • Proliferating Cell Nuclear Antigen / chemistry
  • Proliferating Cell Nuclear Antigen / genetics*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Structure, Quaternary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Syndrome
  • Telangiectasis / genetics


  • Mutant Proteins
  • Proliferating Cell Nuclear Antigen
  • Recombinant Proteins