NBCe1‐B/C Knockout Mice Exhibit Signs Associated with Proximal Renal Tubular Acidosis

The SLC4A4 gene encodes three major variants of the electrogenic Na + /HCO 3 − cotransporter NBCe1: NBCe1‐A, ‐B, and ‐C. NBCe1‐A is expressed in the kidney and contributes to blood pH homeostasis. NBCe1‐B and ‐C are expressed in a diverse array of non‐renal cells and contribute to intracellular pH homeostasis and fluid secretion. Individuals with NBCe1 mutations exhibit proximal renal tubular acidosis (pRTA). Disease signs include low blood pH, diverse ocular abnormalities, and poor dentition. Current treatments for pRTA focus solely on correcting blood pH. Thus it is of interest to determine which signs of pRTA are secondary to the acidosis (due to NBCe1‐A loss) and which are a primary consequence of NBCe1‐B/C loss. There are two previously reported mouse models of the disease: [1] Mice lacking NBCe1 (all variants) that exhibit low blood pH, corneal edema, weak tooth enamel, and impacted intestines; these do not survive beyond 25 days and [2] Mice lacking NBCe1‐A (but expressing NBCe1‐B/C) that exhibit low blood pH and elevated intraocular pressure, but otherwise thrive normally. We have generated a line of mice that, by CRISPR/Cas9 disruption of a common exon, lack NBCe1‐B/C while maintaining expression of NBCe1‐A. These mice have a normal blood pH yet exhibit corneal edema, chalky incisors, and failure to thrive. Thus non‐renal forms of NBCe1 contribute directly to the signs of pRTA and these pathologies, unlikely to be addressed by alkali therapy, require supplemental treatment. Support or Funding Information Start‐up funds from the Dean of the Jacobs School of Medicine and Biomedical Sciences and The Department of Physiology and Biophysics at the University at Buffalo