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J. Biol. Chem., Vol. 279, Issue 50, 52238-52246, December 10, 2004

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A Novel Missense Mutation in the Sodium Bicarbonate Cotransporter (NBCe1/SLC4A4) Causes Proximal Tubular Acidosis and Glaucoma through Ion Transport Defects^*

Dganit Dinour, Min-Hwang Chang¶, Jun-ichi Satoh¶||, Brenda L. Smith¶, Nathan Angle¶, Aaron Knecht, Irina Serban, Eli J. Holtzman, and Michael F. Romero¶**

From the Department of Nephrology and Hypertension, Chaim Sheba Medical Center, Tel-Hashomer, and Tel-Aviv University, 52621 Israel and the ^¶Department of Physiology and Biophysics and ^**Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106-4970

In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na⁺/ 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 ( transport) and membrane currents using microelectrodes. -elicited currents for S427L were 10% of WT NBCe1, and CO₂-induced acidification was 4-fold faster. Na⁺-dependent transport (currents and acidification) was also 10% of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in , indicating that under physiological ion gradient conditions, NaHCO₃ could not move out of cells as is needed for renal 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-hkNBCe1 is unfavorably altered, thereby causing both insufficient absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).

Received for publication, June 14, 2004 , and in revised form, October 1, 2004.

^* This work was supported in part by a Howard Hughes Medical Institute institutional grant to Case Western Reserve University (to M. F. R.) and National Institutes of Health Grant DK-56218 (to M. F. R.). Portions of this work have been reported in preliminary form (15–17). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| Supported by a postdoctoral fellowship from the American Heart Association. Present address: Dept. of Pharmacology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi, Tochigi, Japan.

To whom correspondence should be addressed. Tel.: 216-368-3180; Fax: 216-368-3952; E-mail: Michael.romero{at}case.edu.

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