Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.
Curr Drug Targets. 2011 May;12(5):671-82. doi: 10.2174/138945011795378612.
The ABCC6 gene encodes an organic anion transporter protein, ABCC6/MRP6. Mutations in the gene cause a rare, recessive genetic disease, pseudoxanthoma elasticum, while the loss of one ABCC6 allele is a genetic risk factor in coronary artery disease. We review here the information available on gene structure, evolution as well as the present knowledge on its transcriptional regulation. We give a detailed description of the characteristics of the protein, and analyze the relationship between the distributions of missense disease-causing mutations in the predicted three-dimensional structure of the transporter, which suggests functional importance of the domain-domain interactions. Though neither the physiological function of the protein nor its role in the pathobiology of the diseases are known, a current hypothesis that ABCC6 may be involved in the efflux of one form of Vitamin K from the liver is discussed. Finally, we analyze potential strategies how the gene can be targeted on the transcriptional level to increase protein expression in order to compensate for reduced activity. In addition, pharmacologic correction of trafficking-defect mutants or suppression of stop codon mutations as potential future therapeutic interventions are also reviewed.
ABCC6 基因编码一种有机阴离子转运蛋白 ABCC6/MRP6。该基因的突变会导致一种罕见的隐性遗传疾病——弹性假黄瘤，而失去一个 ABCC6 等位基因则是冠心病的遗传风险因素。我们在这里回顾了有关基因结构、进化以及其转录调控的现有知识。我们详细描述了该蛋白的特征，并分析了转运体三维结构预测中错义疾病突变的分布与蛋白域-域相互作用功能重要性之间的关系。尽管该蛋白的生理功能及其在疾病发病机制中的作用尚不清楚，但目前有一个假设认为 ABCC6 可能参与了一种形式的维生素 K 从肝脏中的流出。最后，我们分析了在转录水平上靶向该基因以增加蛋白表达从而补偿活性降低的潜在策略。此外，还回顾了针对转运缺陷突变体的药物矫正或抑制终止密码子突变作为潜在的治疗干预措施。
