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, Michael F Romero

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Abstract

In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na +/HCO 3 - 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 8427L-NBCe1 in Xenopus oocytes. Function was evaluated by measuring intracellular pH (HCO 3 - transport) and membrane currents using microelectrodes. HCO 3 --elicited currents for S427L were ∼10% of WT NBCe1, and CO 2-induced acidification was ∼4-fold faster. Na +-dependent HCO 3 - transport (currents and acidification) was also ∼10% of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in HCO 3 -, indicating that under physiological ion gradient conditions, NaHCO 3 could not move out of cells as is needed for renal HCO 3 - absorption and ocular pressure homeostasis. I-V analysis without Na + further shows that the S427L-mediated NaHCO 3 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 HCO 3 - absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).

Original languageEnglish (US)
Pages (from-to)52238-52246
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number50
DOIs
StatePublished - Dec 10 2004
Externally publishedYes

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Sodium-Bicarbonate Symporters
Acidification
Ion Transport
Missense Mutation
Acidosis
Glaucoma
Ions
Renal Tubular Acidosis
Kidney
Defects
Rapid thermal annealing
Microelectrodes
Electric potential
Carbon Monoxide
Bicarbonates
Membranes
Viverridae
Fluids
Medical Genetics
Anterior Chamber

ASJC Scopus subject areas

  • Biochemistry

Cite this

A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects. / Dinour, Dganit; Chang, Min Hwang; Satoh, Jun Ichi; Smith, Brenda L.; Angle, Nathan; Knecht, Aaron; Serban, Irina; Holtzman, Eli J.; Romero, Michael F.

In: Journal of Biological Chemistry, Vol. 279, No. 50, 10.12.2004, p. 52238-52246.

Research output: Contribution to journalArticle

Dinour, Dganit ; Chang, Min Hwang ; Satoh, Jun Ichi ; Smith, Brenda L. ; Angle, Nathan ; Knecht, Aaron ; Serban, Irina ; Holtzman, Eli J. ; Romero, Michael F. / A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 50. pp. 52238-52246.
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abstract = "In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na +/HCO 3 - 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 8427L-NBCe1 in Xenopus oocytes. Function was evaluated by measuring intracellular pH (HCO 3 - transport) and membrane currents using microelectrodes. HCO 3 --elicited currents for S427L were ∼10{\%} of WT NBCe1, and CO 2-induced acidification was ∼4-fold faster. Na +-dependent HCO 3 - transport (currents and acidification) was also ∼10{\%} of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in HCO 3 -, indicating that under physiological ion gradient conditions, NaHCO 3 could not move out of cells as is needed for renal HCO 3 - absorption and ocular pressure homeostasis. I-V analysis without Na + further shows that the S427L-mediated NaHCO 3 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 HCO 3 - absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).",
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T1 - A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects

AU - Dinour, Dganit

AU - Chang, Min Hwang

AU - Satoh, Jun Ichi

AU - Smith, Brenda L.

AU - Angle, Nathan

AU - Knecht, Aaron

AU - Serban, Irina

AU - Holtzman, Eli J.

AU - Romero, Michael F

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N2 - In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na +/HCO 3 - 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 8427L-NBCe1 in Xenopus oocytes. Function was evaluated by measuring intracellular pH (HCO 3 - transport) and membrane currents using microelectrodes. HCO 3 --elicited currents for S427L were ∼10% of WT NBCe1, and CO 2-induced acidification was ∼4-fold faster. Na +-dependent HCO 3 - transport (currents and acidification) was also ∼10% of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in HCO 3 -, indicating that under physiological ion gradient conditions, NaHCO 3 could not move out of cells as is needed for renal HCO 3 - absorption and ocular pressure homeostasis. I-V analysis without Na + further shows that the S427L-mediated NaHCO 3 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 HCO 3 - absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).

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