ABC Transporters in Human Disease and Multidrug Resistan

三磷酸腺苷结合盒(ABC)基因家族编码一组不同的转运蛋白，这些转运蛋白将各种化合物泵送到细胞和组织的膜上。几种人类ABC转运蛋白在对化疗药物具有耐药性的肿瘤细胞中过度表达。人类基因组中有48个ABC基因，其中16个基因在影响眼睛、肝脏、胆固醇运输和其他功能的遗传病中发生突变。我们已经证明ABCA3基因在新生儿呼吸衰竭儿童中发生了突变。这些患者在肺表面活性物质的产生方面存在缺陷，肺表面活性物质是由肺泡II型细胞产生的一种富含脂质的分泌物。这些患者的基因突变要么是纯合子，要么是复合杂合子。已鉴定的突变包括保守残基的移码、无义和点突变。对这些患者肺组织的超微分析显示，肺泡细胞中有异常的板层小体。轻度感染的患者被发现存在错义突变，这些突变可能具有部分功能。因此，ABCA3基因的突变可能与其他呼吸道疾病有关。对该基因的进一步研究应能深入了解肺表面活性物质的分泌和肺功能。我们已经鉴定了斑马鱼和被囊珊瑚的ABC基因，这两种生物都是研究基因表达和功能的优秀模式生物。斑马鱼保存了48个人类ABC基因中的32个，其中包括几个引起人类疾病的基因，如ABCC6，但其功能尚不清楚。

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. Several human ABC transporters are overexpressed in tumor cells that are resistant to chemotherapy drugs. There are 48 ABC genes in the human genome and 16 of these are mutated in genetic diseases affecting the eye, liver, cholesterol transport and other functions. We have demonstrated that the ABCA3 gene is mutated in children with neonatal respiratory failure. These patients have defects in the production of lung surfactant, a lipid rich secretion produced by alveolar type II cells. These patients are either homozygous or compound heterozygous for mutations in the gene. The mutations identified include frame shift, nonsense and point mutations in conserved residues. Ultramicroscopic analysis of lung tissue from these patients shows abnormal lamellar bodies in the alveolar cells. Mildly affected patients were identified that have missense mutations that may be partially functional. Thus mutations in the ABCA3 gene may be involved in other respiratory diseases. Further characterization of this gene should yield insights into surfactant secretion and lung function. We have characterized the ABC genes in the zebrafish and the tunicate Ciona, both of which are excellent model organisms for studying gene expression and function. The zebrafish has conserved 32 of the 48 human ABC genes including several such as ABCC6 that cause human disease but whose function is unknown.