Journal Article

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

Shen, Jun, Chang, Bernard S, Ganesh, Vijay S, Grix, Arthur, Walsh, Christopher A, Haddadin, Mary, Topcu, Meral, Barry, Brenda, Bodell, Adria, Gleason, Danielle, Gilmore, Edward C, Barkovich, A James, Hill, R Sean, Caldecott, Keith W, Reynolds, John J, Allen, Kathryn, Eyaid, Wafaa, Marshall, Christine A

2010

Overview

Christopher Walsh and colleagues describe a new recessive genetic disease characterized by microcephaly, early-onset intractable seizures and developmental delay (MCSZ). The authors identify mutations in PNKP that result in this severe disease and show that PNKP mutations disrupt 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 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 692/699/375 / Agriculture / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Causes of / Child / Chromosomes / Chromosomes, Human, Pair 19 / Consanguinity / Deoxyribonucleic acid / Developmental Disabilities - complications / Developmental Disabilities - genetics / DNA / DNA repair / DNA Repair - genetics / DNA Repair Enzymes - genetics / DNA Repair-Deficiency Disorders - complications / DNA Repair-Deficiency Disorders - genetics / Embryo, Mammalian / Family / Female / Free radicals / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Genome-Wide Association Study / Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy / Health aspects / Human Genetics / Humans / Infant / Kinases / letter / Male / Malformations of the nervous system / Medical sciences / Microcephaly / Microcephaly - complications / Microcephaly - genetics / Mutation / Mutation - physiology / Nervous system (semeiology, syndromes) / Neurology / Neurophysiology / Nucleic acids / Pedigree / Phosphatases / Phosphotransferases / Phosphotransferases (Alcohol Group Acceptor) - genetics / Polymorphism, Single Nucleotide / Proteins / Seizures (Medicine) / Seizures - complications / Seizures - genetics