The function of AE1 was to help maintain the cell shape and to exchang Cl- and HCO3-. AE1 is mainly expressed in the erythrocyte and in the acid-secreting, type A intercalated cells of the kidney. It has been demonstrated that nonsense and frameshift mutations of AE1 gene are associated with hereditary spherocytosis (HS) and inherited distal renal tubular acidosis (dRTA). HS and dRTA, however, are almost always mutually exclusive. The first human exception is a single instance of the total absence of AE1 secondary to the mutation Coimbra (V488M) in the homozygous state. We report the second human exception with nearly total absence of AE1 protein due to a novel heterozygous E522K mutation in combination with a heterozygous G701D mutation that show the phenotypes of severe HS and complete dRTA. The protein trafficking and subcellular localization of the kAE1 and kAE1 mutants in transfected MDCK cells were examined. Our results show that AE1 WT, AE1 E522K, or AE1 G701D can form homodimer or heterodimer to each other. For homodimer, kAE1 WT or E522K mutation can traffic to the plasma membrane (44.50% and 33.50%, respectively). Whereas kAE1 G701D or kAE1 E522K&G701D was largely retained in cytoplasm (99.99% and 99.99%, respectively). For heterodimer, our results show that kAE1 E522K/WT or kAE1 G701D/WT traffic to the plasma membrane (40.25% and 43.50%, respectively). Whereas, E522K/G701D also mistargeted to the plasma membrane (0.04%) and retained in the cytoplasm (99.96%, respectively). The protein stability of kAE1 E522K&G701D decreases significantly when compared with that of kAE1 WT. Together with that the kAE1 E522K/G701D largely colocalized with losozyme, these data suggest that the defect of the E522K/G701D trafficking to the plasma membrane and the decrease of protein stability cause the hereditary spherocytosis (HS) and distal renal tubular acidosis (dRTA).
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0730107-140527 |
| Date | 30 July 2007 |
| Creators | Jian, Shu-huei |
| Contributors | Yi-ren Hong, Pei-jung Lu, Jiin-tsuey Cheng, Chung-lung Cho |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0730107-140527 |
| Rights | not_available, Copyright information available at source archive |
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