The molecular genetics of the 22q11-associated schizophrenia
The molecular genetics of the 22q11-associated schizophrenia
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DOI：
10.1016/j.molbrainres.2004.09.029
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发表时间：
2004-12-20
期刊：
影响因子：
--
通讯作者：
Gogos, JA
中科院分区：
文献类型：
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作者：
Karayiorgou, M;Gogos, JA
精神分裂症有很强的遗传成分，但疾病的遗传模式很复杂，很可能涉及多个基因之间的相互作用，也可能涉及环境或随机因素。许多研究表明，22q11缺失综合征（22q11DS）是精神分裂症的一种真正的遗传亚型，因此可能在破译精神分裂症的遗传基础方面发挥极其重要的作用。22q11位点的微缺失与精神分裂症发病风险的惊人增加有关。一些连锁研究也涉及到相同的基因座。对来自1.5Mb关键区域的单个基因的系统检查迄今已鉴定出PRODH和ZDHHC 8是来自该位点的强候选精神分裂症易感基因。这些基因的发现暗示了神经调节氨基酸和蛋白质棕榈酰化对疾病发展的重要性。其他基因，包括编码COMT的基因，已经被候选基因方法所牵连。因此，22q11相关的精神分裂症可能具有连续基因综合征的特征，其中一个以上基因的缺陷导致疾病风险显著增加。单个候选基因的小鼠模型将为研究人员提供开始了解这些基因的功能以及它们如何影响精神分裂症的机会。携带长距离缺失的小鼠模型可能会捕获罪魁祸首基因之间的相互作用，并有助于解释该基因座对精神分裂症高风险的遗传贡献。对22q11DS的深入的人类和动物模型研究有望回答与精神分裂症这一毁灭性疾病有关的关键问题，其原因在很大程度上仍然未知。(C)2004 Elsevier B.V.保留所有权利。
Schizophrenia has a strong genetic component but the mode of inheritance of the disease is complex and in all likelihood involves interaction among multiple genes and also possibly environmental or stochastic factors. A number of studies have shown that the 22q11 deletion syndrome (22q11DS) is a true genetic subtype of schizophrenia and as such may play an extremely important role in deciphering the genetic basis of schizophrenia. Microdeletions of the 22q11 locus are associated with a staggering increased risk to develop schizophrenia. The same locus has also been implicated by some linkage studies. Systematic examination of individual genes from the 1.5 Mb critical region has identified so far the PRODH and ZDHHC8 as strong candidate schizophrenia susceptibility genes from this locus. Discovery of these genes implicates neuromodulatory aminoacids and protein palmitoylation as important for disease development. Other genes, including the gene encoding for COMT, have been implicated by candidate gene approaches. It therefore appears that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome, where deficiency in more than one gene contributes to the strikingly increased disease risk. Mouse models for individual candidate genes will provide the investigators with the opportunity to start understanding the function of these genes and how they may impact on schizophrenia. Mouse models that carry long-range deletions will likely capture the interactions among the culprit genes and help explain the genetic contribution of this locus to the high risk for schizophrenia. In-depth human and animal model studies of 22q11DS promise to answer critical questions relating to the devastating illness of schizophrenia, whose causes remain largely unknown. (C) 2004 Elsevier B.V. All rights reserved.