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neurogenetics

, Volume 14, Issue 1, pp 43–51 | Cite as

Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations

  • Cathryn Poulton
  • Renske Oegema
  • Daphne Heijsman
  • Jeannette Hoogeboom
  • Rachel Schot
  • Hans Stroink
  • Michèl A. Willemsen
  • Frans W. Verheijen
  • Peter van de Spek
  • Andreas Kremer
  • Grazia M. S. ManciniEmail author
Original Article

Abstract

We present a neurodegenerative disorder starting in early childhood of two brothers consisting of severe progressive polyneuropathy, severe progressive cerebellar atrophy, microcephaly, mild epilepsy, and intellectual disability. The cause of this rare syndrome was found to be a homozygous mutation (c.1250_1266dup, resulting in a frameshift p.Thr424GlyfsX48) in PNKP, identified by applying homozygosity mapping and whole-genome sequencing. Mutations in PNKP have previously been associated with a syndrome of microcephaly, seizures and developmental delay (MIM 613402), but not with a neurodegenerative disorder. PNKP is a dual-function enzyme with a key role in different pathways of DNA damage repair. DNA repair disorders can result in accelerated cell death, leading to underdevelopment and neurodegeneration. In skin fibroblasts from both affected individuals, we show increased susceptibility to apoptosis under stress conditions and reduced PNKP expression. PNKP is known to interact with DNA repair proteins involved in the onset of polyneuropathy and cerebellar degeneration; therefore, our findings explain this novel phenotype.

Keywords

DNA repair Microcephaly Polyneuropathy Cerebellar atrophy PNKP MCSZ syndrome 

Notes

Acknowledgments

We thank Dr. N.G. Jaspers at the Department of Genetics, Erasmus Medical Center for critically reading the manuscript. We acknowledge the collaboration of the members of the patients’ family. We thank J. Meulstee for the help with interpretation of EMG data. We also thank Tom de Vries Lentsch for the figures and Petra Veraart for the genealogical study.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

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ESM 1 (DOC 1013 kb)
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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Cathryn Poulton
    • 1
  • Renske Oegema
    • 1
  • Daphne Heijsman
    • 2
  • Jeannette Hoogeboom
    • 1
  • Rachel Schot
    • 1
  • Hans Stroink
    • 3
  • Michèl A. Willemsen
    • 4
  • Frans W. Verheijen
    • 1
  • Peter van de Spek
    • 2
  • Andreas Kremer
    • 2
  • Grazia M. S. Mancini
    • 1
    Email author
  1. 1.Department of Clinical GeneticsErasmus MCRotterdamthe Netherlands
  2. 2.Department of BioinformaticsErasmus MCRotterdamthe Netherlands
  3. 3.Department of NeurologyCanisius-Wilhelmina ZiekenhuisNijmegenthe Netherlands
  4. 4.Department of Pediatric NeurologyUMC St RadboudNijmegenthe Netherlands

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