Hennah William, Thomson Pippa, Peltonen Leena, Porteous David
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
Schizophr Bull. 2006 Jul;32(3):409-16. doi: 10.1093/schbul/sbj079. Epub 2006 May 12.
Schizophrenia and related disorders have a major genetic component, but despite much effort and many claims, few genes have been consistently replicated and fewer have biological support. One recent exception is "Disrupted in Schizophrenia 1" (DISC1), which was identified at the breakpoint on chromosome 1 of the balanced translocation (1;11)(q42.1;q14.3) that co-segregated in a large Scottish family with a wide spectrum of major mental illnesses. Since then, genetic analysis has implicated DISC1 in schizophrenia, schizoaffective disorder, bipolar affective disorder, and major depression. Importantly, evidence is emerging from genetic studies for a causal relationship between DISC1 and directly measurable trait variables such as working memory, cognitive aging, and decreased gray matter volume in the prefrontal cortex, abnormalities in hippocampal structure and function, and reduction in the amplitude of the P300 event-related potential. Further, DISC1 binds a number of proteins known to be involved in essential processes of neuronal function, including neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction. Thus, both genetic and functional data provide evidence for a critical role for DISC1 in schizophrenia and related disorders, supporting the neurodevelopmental hypothesis for the molecular pathogenesis of these devastating illnesses.
精神分裂症及相关障碍具有主要的遗传成分，但尽管付出了诸多努力且有许多说法，但很少有基因能被持续重复验证，且得到生物学支持的更少。最近的一个例外是“精神分裂症1号基因”（DISC1），它是在一个大型苏格兰家族中与多种严重精神疾病共分离的平衡易位（1；11）（q42.1；q14.3）的1号染色体断点处被发现的。从那时起，基因分析表明DISC1与精神分裂症、分裂情感性障碍、双相情感障碍和重度抑郁症有关。重要的是，基因研究正在出现证据，表明DISC1与一些直接可测量的性状变量之间存在因果关系，如工作记忆、认知衰老以及前额叶皮质灰质体积减少、海马结构和功能异常，以及P300事件相关电位的波幅降低。此外，DISC1与许多已知参与神经元功能基本过程的蛋白质结合，包括神经元迁移、神经突生长、细胞骨架调节和信号转导。因此，遗传和功能数据都为DISC1在精神分裂症及相关障碍中的关键作用提供了证据，支持了这些毁灭性疾病分子发病机制的神经发育假说。
