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

Shen, Jun, Gilmore, Edward C, Marshall, Christine A, Haddadin, Mary, Reynolds, John J, Eyaid, Wafaa, Bodell, Adria, Barry, Brenda, Gleason, Danielle, Allen, Kathryn, Ganesh, Vijay S, Chang, Bernard S, Grix, Arthur, Hill, R Sean, Topcu, Meral, Caldecott, Keith W, Barkovich, A James and Walsh, Christopher A (2010) Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nature Genetics, 42 (3). 245-U38. ISSN 1061-4036

Full text not available from this repository.


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(1). 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science
Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 18:16
Last Modified: 08 Oct 2012 08:12
📧 Request an update