Desmopressin as a Promising Therapeutic Approach for the Polyuric Phenotype in Patients with LRBA Deficiency

Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is a rare genetic disorder characterized by immune dysregulation. The immune checkpoint molecule cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fails to perform proper membrane trafficking in the absence of LRBA. In addition to immune cells, LRBA localizes to intracellular vesicles in various epithelial cells; however, its physiological roles have not been accurately deciphered. Our previous studies demonstrated that the LRBA–protein kinase A (PKA) complex facilitates water transport by promoting vesicular trafficking of aquaporin-2 (AQP2) and AQP4 in renal collecting duct cells. Consequently, Lrba knockout mice exhibit vasopressin-resistant polyuria. Despite experimental evidence from mouse models, the renal phenotype in patients with LRBA deficiency remains unclear.

A multicenter design was adopted to ensure accurate patient evaluation, considering the rarity of LRBA deficiency. The participating centers comprised several institutions in Japan as well as the Tehran University of Medical Sciences in Iran. This study included patients diagnosed with LRBA deficiency by genetic analysis between 2012 and 2025. Lrba-R1442Q knock-in mice were generated to investigate the in vivo effects of the mutant LRBA on urinary concentrating ability.

A retrospective registry study revealed that polyuria, defined as urine output ≥2 L/m²/day, was observed in five out of 38 patients. Almost 97% of LRBA-deficient patients experienced chronic diarrhea as a complication; however, urine specific gravity remained consistently low (median 1.009; n = 17), indicating a lack of compensatory concentration. 

Loss-of-function mutations in LRBA have been reported to cause complete degradation of mutant LRBA in peripheral blood mononuclear cells (PBMCs), whereas the expression levels of mutant LRBA, such as LRBA-R1445Q, in the kidney remain unknown. In HEK293T cells, overexpressed murine LRBA-R1442Q (corresponding to human LRBA p.R1445Q) was markedly degraded in lysosomes, and this degradation was rescued by chloroquine treatment. We subsequently generated Lrba-R1442Q knock-in mice. As expected, both PBMCs and the kidneys exhibited reduced LRBA-R1442Q protein levels; however, detectable quantities of the mutant protein were observed, particularly in the kidneys. Immunofluorescence staining revealed that the residual LRBA-R1442Q was primarily localized in the renal inner medulla, a key segment for urine concentration (IMCDs). In contrast to its pronounced loss in the renal cortex, LRBA-R1442Q was incompletely degraded in the IMCDs. LAMP1- and LAMP2-positive lysosomal aggregates were prominent in the IMCDs of Lrba^{R1442Q/R1442Q} knock-in mice. In addition to LRBA’s role in lysosomal homeostasis, it has also been implicated in autophagosome–lysosome fusion. Despite elevated levels of p62 and LC3-II in Lrba^{R1442Q/R1442Q} knock-in mice, colocalization of the autophagy marker LC3 with the lysosomal protein LAMP2 was scarcely detected. These findings indicate that the defective autolysosomal degradation contributes to the retention of LRBA‑R1442Q protein in IMCDs. As a result, urine osmolality rapidly increased within 1 hour after desmopressin administration in these mice, leading to a significant amelioration of polyuria.

LRBA deficiency impairs urinary concentration in both mice and humans. The LRBA-R1442Q mutant retains its function as a scaffold protein for PKA in IMCDs, and Lrba^{R1442Q/R1442Q} knock-in mice—serving as a model of human LRBA deficiency—remain responsive to desmopressin.