Identification and Caracterization of Human ATP-Binding Cassette (ABC) Transporter Genes

Abstract

ATP-binding cassette (ABC) transporters are integral components of most living cells and constitute a large group of structurally related transmembrane proteins. These transporters translocate a wide variety of substrates across cellular membranes, including lipids, ions, sugars, peptides, vitamins, steroid hormones and drugs, such as chemotherapeutics. With a total of 49 known members, the human ABC transporter family is among the largest and most broadly expressed protein superfamilies known. To date, already 16 ABC genes have been causatively linked to completely unrelated groups of monogenetic disorders, including atherosclerosis, eye, liver, lung and skin diseases, and metabolic disorders. Therefore, ABC transporters play important roles in both health and disease. Findings in the presented thesis contributed in identifying and characterizing both known and novel human ABC transporter genes. The thesis describes the gene structure of the gene encoding the A-subclass ABC transporter, ABCA7. Moreover, we report the identification and molecular biological characterizations of the ABC transporters ABCA6 and ABCA9. ABCA6 and ABCA9 form a dense gene cluster together with three other ABCA transporters, ABCA5, ABCA8 and ABCA10, on chromosome 17q24, which we now refer to as “ABCA6-like transporters”. In the last part of the study, we focus on ABC transporter pseudogenes and describe, to the best of our knowledge, all ABC transporter pseudogenes in the human genome. Intriguingly, we found that a large portion of ABC transporter pseudogenes is transcribed. By a siRNA-mediated silencing approach of a transcribed ABC transporter pseudogene, we were able to provide evidence, for the first time in the human organism, for a regulatory interconnection between a transcribed pseudogene and its protein coding counterpart. The results from this thesis may contribute to a better understanding of basal mechanisms involved in the function of ABC transporters and their implication in clinical medicine.