1. Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice
- Author
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Thamer A. Alsufayan, Bianca N. Quade, Emily E Salerno, Cheikh S. Alassane Mballo, Jordan Marshall, Aniko Marshall, Mark D. Parker, and Sangita P Patel
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Mutation, Missense ,Corneal dystrophy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,Medicine ,Animals ,Mice, Knockout ,Analysis of Variance ,biology ,business.industry ,Sodium-Bicarbonate Symporters ,Enamel organ ,Chronic metabolic acidosis ,Metabolic acidosis ,General Medicine ,Acidosis, Renal Tubular ,Tooth enamel ,medicine.disease ,Bicarbonates ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Basic Research ,Phenotype ,Gene Expression Regulation ,Nephrology ,Failure to thrive ,biology.protein ,Acidosis, Respiratory ,medicine.symptom ,Blood Gas Analysis ,business ,SLC4A4 ,Acidosis ,Proximal renal tubular acidosis ,030217 neurology & neurosurgery - Abstract
Background The SLC4A4 gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in SLC4A4 causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning. Alkali therapy remains the preferred treatment for pRTA, but it is unclear which nonrenal signs are secondary to acidemia and which are a direct consequence of NBCe1 loss from nonrenal sites (such as the eye and enamel organ) and therefore require separate therapy. SLC4A4 encodes three major NBCe1 variants: NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A is expressed in proximal tubule epithelia; its dysfunction causes the plasma bicarbonate insufficiency that underlies acidemia. NBCe1-B and NBCe1-C exhibit a broad extra-proximal-tubular distribution. Methods To explore the consequences of Nbce1b/c loss in the absence of acidemia, we engineered a novel strain of Nbce1b/c-null mice and assessed them for signs of pRTA. Results Nbce1b/c-null mice have normal blood pH, but exhibit increased mortality, growth retardation, corneal edema, and tooth enamel defects. Conclusions The correction of pRTA-related acidemia should not be considered a panacea for all signs of pRTA. The phenotype of Nbce1b/c-null mice highlights the physiologic importance of NBCe1 variants expressed beyond the proximal tubular epithelia and potential limitations of pH correction by alkali therapy in pRTA. It also suggests a novel genetic locus for corneal dystrophy and enamel hypomineralization without acidemia.
- Published
- 2019