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,...
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| Published in | Nature genetics Vol. 42; no. 3; pp. 245 - 249 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.03.2010
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Summary: | 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. |
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| Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Author contribution: J.S. helped characterize MCSZ syndrome, identified MCSZ locus and calculated LOD scores, sequenced genes in MCSZ locus to identify PNKP mutations, wrote the manuscript, E.C.G. helped characterize MCSZ syndrome, identified moderately affected MCSZ family, performed RT-PCR on moderately affected family, performed comet assays, organized and analyzed sequenom experiments, did analysis of PNKP mutation, performed mouse RNAi experiments, helped perform mouse in situs, wrote the manuscript, C.A.M. sequenced genes in MCSZ locus to identify PNKP mutations and helped perform human in situs, M.H. identified patients and provided clinical information, J.J.R. performed PNKP Western blot and confirmatory comet assays, W.E. identified patients and provided clinical information, A.B. organized clinical information and patient samples, B.B. organized clinical information and patient samples, D.G. organized patient samples and helped perform sequenome experiments, K.A. organized patient samples and helped perform sequencing experiments, V.S.G. helped analyze sequenom experiments, B.S.C. helped organize clinical information to identify MCSZ syndrome, A.G. identified patients and provided clinical information, R.S.H. helped organize genetic data and calculate LOD scores, M.T. identified patients and provided clinical information, K.W.C. advised on comet assays, supervised PNKP Western blot and edited manuscript, A.J.B. characterized MRIs for patient classification, C.A.W. directed overall research and wrote the manuscript. These authors contributed equally to the work. Current address: Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA, USA |
| ISSN: | 1061-4036 1546-1718 1546-1718 |
| DOI: | 10.1038/ng.526 |