Porteous David J, Thomson Pippa, Brandon Nicholas J, Millar J Kirsty
Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Crewe Road South, Edinburgh.
Biol Psychiatry. 2006 Jul 15;60(2):123-31. doi: 10.1016/j.biopsych.2006.04.008.
In the developing field of biological psychiatry, DISC1 stands out by virtue of there being credible evidence, both genetic and biological, for a role in determining susceptibility to schizophrenia and related disorders. We highlight the methodologic paradigm that led to identification of DISC1 and review the supporting genetic and biological evidence. The original finding of DISC1 as a gene disrupted by a balanced translocation on chromosome 1q42 that segregates with schizophrenia, bipolar disorder, and recurrent major depression has sparked a number of confirmatory linkage and association studies. These indicate that DISC1 is a generalizable genetic risk factor for psychiatric illness that also influences cognition in healthy subjects. DISC1 has also been shown to interact with a number of proteins with neurobiological pedigrees, including Ndel1 (NUDEL), a key regulator of neuronal migration with endo-oligopeptidase activity, and PDE4B, a phosphodiesterase that is critical for cyclic adenosine monophosphate signaling and that is directly linked to learning, memory, and mood. Both are potential "drug" targets. DISC1 has thus emerged as a key molecular player in the etiology of major mental illness and in normal brain processes.
在生物精神病学这一发展中的领域，DISC1因有可靠的遗传和生物学证据表明其在决定对精神分裂症及相关疾病的易感性方面发挥作用而格外突出。我们着重介绍了导致DISC1被识别的方法学范式，并回顾了相关的遗传和生物学支持证据。DISC1最初是作为一个在1号染色体1q42上因平衡易位而被破坏的基因被发现的，该基因与精神分裂症、双相情感障碍和复发性重度抑郁症相关联，这引发了许多验证性的连锁和关联研究。这些研究表明，DISC1是一种可推广的精神疾病遗传风险因素，它也会影响健康受试者的认知。DISC1还被证明与许多具有神经生物学谱系的蛋白质相互作用，包括Ndel1（NUDEL），一种具有内肽酶活性的神经元迁移关键调节因子，以及PDE4B，一种对环磷酸腺苷信号传导至关重要且与学习、记忆和情绪直接相关的磷酸二酯酶。这两者都是潜在的“药物”靶点。因此，DISC1已成为重大精神疾病病因学和正常脑过程中的关键分子参与者。
