Defective SLC4A4 does not cotransport Na+ with 3HCO3-

Stable Identifier
Reaction [transition]
Homo sapiens
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Members 4, 5, 7 and 9 of the SLC4A family couple the transport of bicarbonate (HCO3-) with sodium ions (Na+). SLC4A4 (aka NBCe1) is an electrogenic Na+/HCO3- cotransporter with a stoichiometry of 1:3. SLC4A4 is expressed in the kidney and pancreas, with lesser expression in many other tissues. Mutations in SLC4A4 can cause permanent isolated proximal renal tubular acidosis with ocular abnormalities and mental retardation (pRTA-OA), a rare autosomal recessive syndrome characterised by short stature, proximal renal tubular acidosis, mental retardation, bilateral glaucoma, cataracts and bandkeratopathy. pRTA results from the failure of the proximal tubular cells to reabsorb filtered HCO3- from urine, leading to urinary HCO3- wasting and subsequent acidemia. HCO3- also needs to move out of cells in the eye, thus failure to do so can affect ocular pressure homeostasis. Mutations causing pRTA-OA include Q29*, R298S, S427L, T485S, R510H, W516*, A799V and a 65bp-del (Igarashi et al. 1999, Dinour et al. 2004, Horita et al. 2005, Lo et al. 2011, Suzuki et al. 2010).
Literature References
PubMed ID Title Journal Year
21228764 Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis

Horita, S, Lin, SW, Lo, YF, Yamazaki, O, Fujita, T, Tsai, JD, Lin, SH, Yu, IS, Usui, T, Seki, G, Yang, SS, Yamada, H

Kidney Int. 2011
15471865 A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects

Smith, BL, Satoh, J, Chang, MH, Holtzman, EJ, Angle, N, Serban, I, Knecht, A, Dinour, D, Romero, MF

J. Biol. Chem. 2004
10545938 Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities

Tozawa, F, Cha, SH, Igarashi, T, Satoh, H, Kanai, Y, Seki, G, Shiobara, M, Shimadzu, M, Endou, H, Kunimi, M, Mori, T, Tsukamoto, K, Inatomi, J, Sekine, T

Nat Genet 1999
20798035 Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine

Horita, S, Shimadzu, M, Shiohara, M, Fujita, T, Van Paesschen, W, Legius, E, Mikoshiba, K, De Jonghe, P, Bergmans, BA, Fujimoto, I, Sekine, T, Al-Gazali, L, Riant, F, Li, Y, Seki, G, Igarashi, T, Suzuki, M, Braverman, N, Stalmans, I, Yamada, H

Proc. Natl. Acad. Sci. U.S.A. 2010
15930088 Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities

Moriyama, N, Dasouki, M, Horita, S, Shimadzu, M, Fujita, T, Sekine, T, Al-Gazali, L, Endo, Y, Ekim, M, Inatomi, J, Seki, G, Igarashi, T, Yamada, H

J. Am. Soc. Nephrol. 2005
Catalyst Activity

sodium:bicarbonate symporter activity of SLC4A4 mutants [plasma membrane]

Normal reaction
Functional status

Loss of function of SLC4A4 mutants [plasma membrane]

Name Identifier Synonyms
renal tubular acidosis DOID:14219
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