Comparative Study of Men and Knock-in Mice Expressing Red Cell Glycophorin B-A-B hybrid Protein Identifies Physiological Functions of SLC4A1 (band 3)

Abstract

GP.Mur is a common Southeast Asian red blood cell (RBC) type, with 4.7% prevalence in Taiwan (compared to 5.8% AB blood type). In people with the GP.Mur (glycophorin B-A-B hybrid) type, their expression of Cl−/HCO3− anion exchanger-1 (AE1; SLC4A1; band 3) on the RBC membrane is increased. Glycophorin A, as well as this glycophorin B-A-B variant, are chaperone proteins that promote SLC4A1 folding and protein formation by 10% or more. Healthy people with the GP.Mur blood type exhibit two unique physiological features: (1) slightly higher blood pressure, and (2) more effcient CO2 excretion. Human and mouse lacking SLC4A1 cannot survive postnatally. As the physiological impacts and mechanisms of SLC4A1 are unclear, we created a knock-in mouse model of human GYP.Mur. To verify whether these physiological features could indeed be the direct consequences of GYP.Mur expression, we tested the knock-in mice by (1) blood pressure measurements with antihypertensive drug challenges, and (2) whole-body plethysmorgraphy (WBP)-respiration measurements. We found that GYP.Mur knock-in mice also expressed more SLC4A1 on the RBC membrane. The knock-in mice exhibited significantly higher mean arterial pressure (MAP) than age-matched control C57BL/6J mice, with differential antihypertensive sensitivities. In WBP measurements on freely-moving mice, GYP.Mur knock-in and the control mice also showed differential respiratory patterns, which were diminished with acetazolamide pretreatments. Thus, GYP.Mur knock-in mice recapitulates the major phenotypes of people carrying the GP.Mur blood type. Taiwan Ministry of Science & Technology (MOST 108-2628-B-195-001; 109-2628-B-195-001; 110-2628-B-195-001); Taiwan MacKay Memorial Hospital. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.