Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
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DNA完整性的维持对所有细胞类型都至关重要，但神经元对DNA修复基因的突变特别敏感，这会导致发育异常和神经退行性变。我们描述了一种以前未知的常染色体隐性遗传病，其特征是小头畸形，早发性，顽固性癫痫发作和发育迟缓（表示MCSZ）。在近亲家庭中使用全基因组连锁分析，我们将疾病位点定位到染色体19q13.33，并确定了导致严重神经系统疾病的PNKP（多核苷酸激酶3′-磷酸酶）的多个突变;相反，剪接突变与更温和的症状相关。出乎意料的是，尽管携带这种突变的个体的细胞对辐射和其他DNA损伤剂敏感，但还没有这样的个体患上癌症或免疫缺陷。与其他影响人类的DNA修复缺陷不同，PNKP突变普遍导致严重的癫痫发作。MCSZ患者的神经系统异常可能反映了PNKP在几种DNA修复途径中的作用。
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 inPNKP(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,PNKPmutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.