PIPK2A, a candidate gene for schizophrenia: impact of DNA polymorphisms on gene- and protein expression and -function

精神分裂症是一种毁灭性的精神障碍，不仅对个人，而且对家庭和社区都有严重影响。这种疾病在全世界所有人口中的流行率约为0.5%。超过20万澳大利亚人患有精神分裂症，每年给澳大利亚社区造成近20亿美元的损失。精神分裂症的原因仍不清楚。现在，人们一致认为，先天(遗传因素)和后天(环境影响)在这种疾病的发展中发挥了作用。遗传因素的证据已经获得，并被家庭、双胞胎和收养研究一致证实。经过多年的研究，通过对具有多个受影响成员的大家庭样本进行基因寻找，已经获得了几个与精神分裂症易感性有关的基因的证据。然而，这些基因必须被考虑为候选基因，直到人们更多地了解它们对导致精神分裂症障碍的大脑功能的影响。我们对包括我们在内的几个群体进行了连锁分析，发现了染色体10p上的一个基因座。我们获得了编码磷脂酰基-4-磷酸-5-激酶酶基因的DNA序列变异与精神分裂症相关的统计证据。这种酶是参与细胞信号转导的肌醇磷脂途径的关键组成部分。我们的目标是确定通路中可能存在的功能障碍。我们将寻找与酶的功能或功能障碍有关的突变。我们将研究淋巴母细胞培养和死后脑组织中的基因和蛋白质表达以及酶功能。我们的最终目标是确定细胞内信号的可能损害，从而确定分子靶点，以开发新的和特定的药物治疗，有可能取代目前可用的药物，这些药物是以症状为导向的，通常伴随着严重的不良反应。

Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the disorder. Evidence for genetic factors has been obtained and consistently confirmed by family-, twin-, and adoption studies. After many years of research, evidence for several genes, conferring susceptibility to schizophrenia, has been obtained by gene finding approaches applied to large family samples with multiple affected members. However, these genes have to be considered as candidates until more is known about their impact on brain function resulting in schizophrenic disorders. We have dissected a gene locus on chromosome 10p detected by linkage analysis by several groups including ourselves. We obtained statistical evidence for association of DNA sequence variants in the gene encoding the enzyme phosphatidyl-4-phosphate 5-kinase with schizophrenia. This enzyme is a critical component of the phosphoinositide pathways, which are involved in cell signalling. Our aim is to identify a possible dysfunction in the pathways. We will search for mutations involved in function or dysfunction of the enzyme. We will investigate gene- and protein expression and enzyme function in lymphoblast cell cultures and in post mortem brain tissue. Our ultimate goal is to characterise the possible impairment of intracellular cell signalling and thus identify molecular targets for development of novel and specific pharmacological treatments that have the potential to replace the currently available medication which is symptom-oriented and usually accompanied by severe adverse effects.