title: Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
abstract: 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.
authors.affiliation: [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.
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Edward C
authors.initials: EC
authors.lastname: Gilmore
authors.forename: Christine A
authors.initials: CA
authors.lastname: Marshall
authors.forename: Mary
authors.initials: M
authors.lastname: Haddadin
authors.forename: John J
authors.initials: JJ
authors.lastname: Reynolds
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.forename: Adria
authors.initials: A
authors.lastname: Bodell
authors.forename: Brenda
authors.initials: B
authors.lastname: Barry
authors.forename: Danielle
authors.initials: D
authors.lastname: Gleason
authors.forename: Kathryn
authors.initials: K
authors.lastname: Allen
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Ganesh
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Chang
authors.forename: Arthur
authors.initials: A
authors.lastname: Grix
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Meral
authors.initials: M
authors.lastname: Topcu
authors.forename: Keith W
authors.initials: KW
authors.lastname: Caldecott
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: 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*
chemical_list: C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D045643:DNA Repair Enzymes