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

PIPK2A，精神分裂症的候选基因：DNA 多态性对基因和蛋白质表达及功能的影响

• 批准号: nhmrc : 404012
• 负责人: Prof Assen Jablensky
• 金额: $ 30.27万
• 依托单位: The University of Western Australia
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/pipk2a-candidate-gene-expression-function/81142
• 关键词: PIPK2A; candidate; gene; schizophrenia; impact

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.

精神分裂症是一种毁灭性的精神障碍，不仅对个人，而且对家庭和社区产生严重影响。在世界范围内，该病的患病率在所有人群中约为0.5%。超过20万澳大利亚人患有精神分裂症，每年给澳大利亚社会造成近20亿澳元的损失。精神分裂症的病因尚不清楚。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得到了家庭、双胞胎和收养研究的一致证实。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发现，已经获得了几个基因赋予精神分裂症易感性的证据。然而，这些基因必须被视为候选基因，直到更多地了解它们对导致精神分裂症的大脑功能的影响。我们已经解剖了染色体10 p上的一个基因位点，该位点是由包括我们在内的几个小组通过连锁分析检测到的。我们获得的统计学证据关联的DNA序列变异的基因编码的酶磷脂酰-4-磷酸5-激酶与精神分裂症。这种酶是参与细胞信号传导的磷酸肌醇途径的关键组分。我们的目的是确定可能的功能障碍的途径。我们将寻找与酶的功能或功能障碍有关的突变。我们将研究基因和蛋白质的表达和酶的功能在淋巴母细胞培养和死后的脑组织。我们的最终目标是确定细胞内信号传导的可能损害，从而确定用于开发新的和特定的药理学治疗的分子靶点，这些药物有可能取代目前可用的药物，这些药物是以药物为导向的，通常伴有严重的不良反应。