A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects

被引:136
|
作者
Dinour, D
Chang, MH
Satoh, J
Smith, BL
Angle, N
Knecht, A
Serban, I
Holtzman, EJ
Romero, MF [1 ]
机构
[1] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA
[3] Tel Aviv Univ, IL-52621 Tel Hashomer, Israel
[4] Chaim Sheba Med Ctr, Dept Hypertens & Nephrol, IL-52621 Tel Hashomer, Israel
关键词
D O I
10.1074/jbc.M406591200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na+/HCO3- cotransporter (NBCe1/SLC4A4). Recently, human genetics revealed that NBCe1 is the major renal contributor to this process. Homozygous point mutations in NBCe1 cause proximal renal tubular acidosis (pRTA), glaucoma, and cataracts (Igarashi, T., Inatomi, J., Sekine, T., Cha, S. H., Kanai, Y., Kunimi, M., Tsukamoto, K., Satoh, H., Shimadzu, M., Tozawa, F., Mori, T., Shiobara, M., Seki, G., and Endou, H. (1999) Nat. Genet. 23, 264-266). We have identified and functionally characterized a novel, homozygous, missense mutation (S427L) in NBCe1, also resulting in pRTA and similar eye defects without mental retardation. To understand the pathophysiology of the syndrome, we expressed wild-type (WT) NBCe1 and S427L-NBCe1 in Xenopus oocytes. Function was evaluated by measuring intracellular pH (HCO3- transport) and membrane currents using micro-electrodes. HCO3--elicited currents for S427L were similar to10% of WT NBCe1, and CO2-induced acidification was similar to4-fold faster. Na+-dependent HCO3- transport (currents and acidification) was also similar to10% of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in HCO3-, indicating that under physiological ion gradient conditions, NaHCO3 could not move out of cells as is needed for renal HCO3- absorption and ocular pressure homeostasis. I-V analysis without Na+ further shows that the S427L-mediated NaHCO3 efflux mode is depressed or absent. These experiments reveal that voltage- and Na+-dependent transport by S427L-hkN-BCe1 is unfavorably altered, thereby causing both insufficient HCO3- absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).
引用
收藏
页码:52238 / 52246
页数:9
相关论文
共 34 条
  • [31] The sodium-bicarbonate cotransporter NBCe2 (slc4a5) expressed in human renal proximal tubules shows increased apical expression under high-salt conditions
    Gildea, John J.
    Xu, Peng
    Carlson, Julia M.
    Gaglione, Robert T.
    Wang, Dora Bigler
    Kemp, Brandon A.
    Reyes, Camellia M.
    McGrath, Helen E.
    Carey, Robert M.
    Jose, Pedro A.
    Felder, Robin A.
    AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2015, 309 (11) : R1447 - R1459
  • [32] A Novel Compound Heterozygous Mutation in SLC4A1 Gene Causing Severe Hereditary Spherocytosis and Distal Renal Tubular Acidosis
    Xue Tang
    Xia Guo
    Ju Gao
    The Indian Journal of Pediatrics, 2020, 87 : 233 - 234
  • [33] A Novel Compound Heterozygous Mutation in SLC4A1 Gene Causing Severe Hereditary Spherocytosis and Distal Renal Tubular Acidosis
    Tang, Xue
    Guo, Xia
    Gao, Ju
    INDIAN JOURNAL OF PEDIATRICS, 2020, 87 (03): : 233 - 234
  • [34] A NOVEL ASSOCIATION BETWEEN VAL2ALA MISSENSE MUTATION IN ATP6V0A4 GENE AND GLAUCOMA, PHACODONESIS AND CATARACT IN PATIENTS WITH DISTAL RENAL TUBULAR ACIDOSIS
    Sav, Nadide Melike
    Yildiz, Bilal
    Yildirim, Nilgun
    PEDIATRIC NEPHROLOGY, 2015, 30 (09) : 1671 - 1671