ABC Transporters in Human Disease and Multidrug Resistan

ATP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穿过细胞和组织的膜。几种人ABC转运蛋白在对化疗药物有抗性的肿瘤细胞中过表达。人类基因组中有48个ABC基因，其中16个在影响眼睛，肝脏，胆固醇运输和其他功能的遗传疾病中发生突变。我们已经证明，ABCA3基因突变的新生儿呼吸衰竭的儿童。这些患者在肺表面活性物质的产生方面有缺陷，肺表面活性物质是由肺泡II型细胞产生的富含脂质的分泌物。这些患者是基因突变的纯合子或复合杂合子。鉴定的突变包括移码、无义和保守残基的点突变。对这些患者的肺组织进行超微分析，发现肺泡细胞中存在异常板层小体。轻度受影响的患者被鉴定为具有可能部分功能的错义突变。因此，ABCA3基因的突变可能与其他呼吸系统疾病有关。该基因的进一步表征将有助于深入了解表面活性物质分泌和肺功能。我们的特点是在斑马鱼和被囊海鞘，这两个都是很好的模式生物研究基因表达和功能的ABC基因。斑马鱼保留了48个人类ABC基因中的32个，包括几个如ABCC6，这些基因会导致人类疾病，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.