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Mutations in the sodium bicarbonate cotransporter NBCe1 ( SLC4A4 ) cause proximal renal tubular acidosis (pRTA). We recently described a novel pRTA mutation p.Gln913Arg (Q913R), inherited in compound heterozygous form with p.Arg510His (R510H). Q913R causes intracellular retention of NBCe1 and a ‘gain of function’ Cl −  leak. To learn more about the importance of glutamine at position 913, we substituted a variety of alternative amino-acid residues (Cys, Glu, Lys, Leu, Ser) at position 913. Studying cRNA-injected  Xenopus  oocytes by voltage clamp, we find that most  de novo  mutants exhibit close-to-normal NBCe1 activity; only Q913K expresses a Cl −  leak. Studying transiently-transfected, polarised kidney cells by fluorescence microscopy we find that most  de novo  mutants (except Q913E) are intracellularly retained. A 3D homology model predicts that Gln913 is located in the gating domain of NBCe1 and neighbours the 3D space occupied by another pRTA-associated residue (Arg881), highlighting an important and conformationally-sensitive region of NBCe1. We conclude that the intracellular retention of Q913R is caused by the loss of Gln at position 913, but that the manifestation of the Cl −  leak is related to the introduction of Arg at position 913. Our findings will inform future studies to elucidate the nature and the consequences of the leak.

scientific reports

The role of disease-linked residue glutamine-913 in support of the structure and function of the human electrogenic sodium/bicarbonate cotransporter NBCe1-A