ABC Transporters in Human Disease and Multidrug Resistan

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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.