Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
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.
Shen
Jun
J
[1] Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA. [2] These authors contributed equally to the work.
Gilmore
Edward C
EC
Marshall
Christine A
CA
Haddadin
Mary
M
Reynolds
John J
JJ
Eyaid
Wafaa
W
Bodell
Adria
A
Barry
Brenda
B
Gleason
Danielle
D
Allen
Kathryn
K
Ganesh
Vijay S
VS
Chang
Bernard S
BS
Grix
Arthur
A
Hill
R Sean
RS
Topcu
Meral
M
Caldecott
Keith W
KW
Barkovich
A James
AJ
Walsh
Christopher A
CA
D002648:Child; D002888:Chromosomes, Human, Pair 19; D003241:Consanguinity; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D049914:DNA Repair-Deficiency Disorders / Q000150:complications / Q000235:genetics*; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D004622:Embryo, Mammalian; D005190:Family; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012640:Seizures / Q000150:complications / Q000235:genetics*
C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D045643:DNA Repair Enzymes