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The previously undescribed heterozygous missense mutation E758K was discovered in the human AE1/SLC4A1/band 3 gene in two unrelated patients with well-compensated hereditary spherostomatocytic anemia (HSt). Oocyte surface expression of AE1 E758K, in contrast to that of wild-type AE1, required coexpressed glycophorin A (GPA). The mutant polypeptide exhibited, in parallel, strong GPA dependence of DIDS-sensitive ³⁶Cl⁻ influx, trans-anion-dependent ³⁶Cl⁻ efflux, and Cl⁻/HCO₃⁻ exchange activities at near wild-type levels. AE1 E758K expression was also associated with GPA-dependent increases of DIDS-sensitive pH-independent SO₄²⁻ uptake and oxalate uptake with altered pH dependence. In marked contrast, the bumetanide- and ouabain-insensitive ⁸⁶Rb⁺ influx associated with AE1 E758K expression was largely GPA-independent in Xenopus oocytes and completely GPA-independent in …