De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia

Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.

精神分裂症很可能是由尚未充分了解的遗传和环境因素导致的。我们对285名对照者和185名父母未患病的精神分裂症患者的编码突触蛋白SHANK3的基因进行了研究。在两个家族中发现了两个新生突变（R1117X和R536W），其中一个突变在三个患病的兄弟中被发现，这表明存在生殖系嵌合现象。斑马鱼和大鼠海马神经元实验揭示了R1117X突变体导致的行为和分化缺陷。由于此前在自闭症中报道过SHANK3的突变，在具有精神分裂症表型的个体中出现SHANK3突变表明这两种神经发育障碍之间存在分子遗传联系。