Desmopressin Improves Urinary Concentrating Defect Caused by LRBA Deficiency

Background: Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) is indispensable for membrane trafficking of a checkpoint immune molecule, CTLA-4, in regulatory T cells. Biallelic pathogenic variants in LRBA abolish LRBA protein expression, resulting in immune dysregulation and chronic diarrhea; however, the renal phenotype of LRBA deficiency remains unknown. We discovered the LRBA-protein kinase A (PKA) complex at renal recycling endosomes which promotes membrane trafficking of aquaporin-2 (AQP2) water channels. In this study, we further investigate physiological roles of LRBA in the kidneys to determine renal phenotypes of patients with LRBA deficiency. Methods: Membrane fraction of kidneys from Lrba-/- mice was analyzed by a quantitative proteomic analysis. We generated LRBA-deficient mice carrying pathogenic missense mutation of Lrba (p.R1442Q, which corresponds to the human LRBA p.R1445Q). The observational registry study was designed to assess urinary concentrating ability of patients with LRBA deficiency. Results: Proteomic analysis detected 12 membrane proteins whose protein expression levels were decreased in Lrba-/- mice. AQP4 was the primary candidate protein under direct regulation by LRBA because it comprises LRBA-binding motif, Y277MEV, in its C-tail. LRBA bound to AQP4-WT, but not to AQP4-Y277F. An alanine substitution of the PKA phosphorylation residue, AQP4-S276, also dissociated the LRBA-AQP4 interaction. Overexpression of LRBA increased cell surface expression of AQP4 in vitro. Contrastingly, Lrba knockout impaired AQP2 and AQP4 activities, causing decline in maximum urine osmolality (WT: 4045±657.01 mOsm/kg, Lrba-/-: 1408±207.28 mOsm/kg). Of note, urinary concentrating defect in LRBA-deficient mice was alleviated by desmopressin treatment (LrbaR1442Q/R1442Q: 2748±151.78 mOsm/kg). Although the registry study showed 97% of LRBA deficiency patients had chronic diarrhea, their urine specific gravity was relatively low (median, 1.008, n=17). Conclusion: LRBA deficiency patients are at high risk of dehydration due to chronic diarrhea and recurrent infections. Low urine concentrating ability leads to deterioration in negative body fluid balance. Desmopressin is a promising treatment for dehydration resulting from LRBA deficiency.