ABC TRANSPORTERS IN HUMAN DISEASE AND DRUG RESISTANCE

人类疾病和耐药性中的 ABC 转运蛋白

• 批准号: 6100857
• 负责人: M DEAN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6100857
• 关键词: adenosine triphosphate; gene expression; genetic disorder; genetic mapping; genetic models; human genetic material tag; macular degeneration; membrane transport proteins; model design /development; molecular cloning; multidrug resistance; neoplasm /cancer genetics; pharmacogenetics

The ATP-binding cassette (ABC) gene family encodes a diverse group of transporter proteins that pump a wide variety of compounds across the membranes of cells and tissues. Human ABC genes are involved in a number of diseases, including cystic fibrosis, adrenoleuko-dystrophy, and familial persistent hyperinsulinemic hypoglycemia. Resistance of tumors to multiple drugs (multidrug resistance, MDR) is a major limitation of cancer chemotherapy. MDR is associated in certain tumors with the overexpression of the P-glycoprotein/(PGP)MDR and multidrug resistance- related protein (MRP) genes. PGP and MRP are ABC family transporters. We have previously identified over 21 new human ABC genes. The genetic location of each of these genes as well as their expression pattern has been determined. One of these genes, ABCR, is expressed exclusively in the retina. The gene was mapped to chromosome 1p13- 21, the location of the Stargardt macular dystrophy (STGD1) gene, a recessive disorder causing vision loss in children. We identified a total of 19 different mutations in the ABCR gene in STGD1 patients, including several frame- shift and non-sense alleles. STGD1 is phenotypically similar to age- related macular degeneration (AMD), a common form of retinal degeneration that occurs in people over age 65. We examined a cohort of 167 AMD patients and found that 16% of them had mutations in the ABCR gene. Understanding the role of mutations in this gene in STGD1 and AMD, and identifying the normal function of ABCR should shed light on the development of macular degeneration. Further characterization of other ABC genes may provide information on other human diseases and neoplasms.

ATP 结合盒 (ABC) 基因家族编码多种 转运蛋白可将多种化合物泵送至整个细胞 细胞和组织的膜。人类 ABC 基因参与了许多 疾病，包括囊性纤维化、肾上腺脑白质营养不良和 家族性持续性高胰岛素性低血糖。肿瘤的抵抗力 对多种药物（多重耐药性，MDR）的主要限制 癌症化疗。 MDR 与某些肿瘤相关 P-糖蛋白/(PGP)MDR的过度表达和多药耐药性- 相关蛋白（MRP）基因。 PGP 和 MRP 是 ABC 家族转运蛋白。 我们之前已经鉴定出超过 21 个新的人类 ABC 基因。遗传性 每个基因的位置及其表达模式 已确定。这些基因之一 ABCR 只在 视网膜。该基因定位于染色体 1p13-21，即 Stargardt 黄斑营养不良 (STGD1) 基因，一种隐性遗传疾病 导致儿童视力丧失。我们总共确定了 19 种不同的 STGD1 患者的 ABCR 基因突变，包括几个框架- 移位和无义等位基因。 STGD1 在表型上与年龄相似 相关黄斑变性 (AMD)，一种常见的视网膜病变 65 岁以上人群发生的退化。我们检查了一组 167名AMD患者，发现其中16%的ABCR有突变 基因。了解该基因突变在 STGD1 和 AMD 中的作用， 确定 ABCR 的正常功能应该有助于阐明 黄斑变性的发展。其他的进一步表征 ABC 基因可能提供有关其他人类疾病和肿瘤的信息。