Oti M, Snel B, Huynen M A, Brunner H G
J Med Genet. 2006 Aug;43(8):691-8. doi: 10.1136/jmg.2006.041376. Epub 2006 Apr 12.
The responsible genes have not yet been identified for many genetically mapped disease loci. Physically interacting proteins tend to be involved in the same cellular process, and mutations in their genes may lead to similar disease phenotypes.
To investigate whether protein-protein interactions can predict genes for genetically heterogeneous diseases.
72,940 protein-protein interactions between 10,894 human proteins were used to search 432 loci for candidate disease genes representing 383 genetically heterogeneous hereditary diseases. For each disease, the protein interaction partners of its known causative genes were compared with the disease associated loci lacking identified causative genes. Interaction partners located within such loci were considered candidate disease gene predictions. Prediction accuracy was tested using a benchmark set of known disease genes.
Almost 300 candidate disease gene predictions were made. Some of these have since been confirmed. On average, 10% or more are expected to be genuine disease genes, representing a 10-fold enrichment compared with positional information only. Examples of interesting candidates are AKAP6 for arrythmogenic right ventricular dysplasia 3 and SYN3 for familial partial epilepsy with variable foci.
Exploiting protein-protein interactions can greatly increase the likelihood of finding positional candidate disease genes. When applied on a large scale they can lead to novel candidate gene predictions.
许多通过基因定位的疾病位点的致病基因尚未被鉴定出来。物理上相互作用的蛋白质往往参与相同的细胞过程，其基因突变可能导致相似的疾病表型。
研究蛋白质 - 蛋白质相互作用是否能够预测基因异质性疾病的致病基因。
利用10894种人类蛋白质之间的72940种蛋白质 - 蛋白质相互作用，在432个位点中搜索代表383种基因异质性遗传性疾病的候选致病基因。对于每种疾病，将其已知致病基因的蛋白质相互作用伙伴与尚未鉴定出致病基因的疾病相关位点进行比较。位于这些位点内的相互作用伙伴被视为候选致病基因预测。使用一组已知致病基因的基准集测试预测准确性。
做出了近300个候选致病基因预测。其中一些后来得到了证实。平均而言，预计10%或更多是真正的致病基因，与仅依靠定位信息相比，富集了10倍。有趣的候选基因例子包括致心律失常性右心室发育不良3的AKAP6和家族性部分性癫痫伴可变病灶的SYN3。
利用蛋白质 - 蛋白质相互作用可以大大增加找到定位候选致病基因的可能性。大规模应用时，它们可以导致新的候选基因预测。
