TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV

Background: Loss of function mutations in the lysosomal channel TRPML-1 cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood.

Methods: A cross-sectional review of medical records from 21 MLIV patients (ages 3-43 years) was conducted to assess kidney function impairment. Additionally, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo renal filtration measurements.

Results: Of the 21 MLIV patients only adults were diagnosed with stage 2-3 chronic kidney disease. Laboratory abnormalities included decreased eGFR, higher levels BUN/Creatine in bloodand proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor-mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. Additionally, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the pro-inflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, AAV-mediated TRPML-1 gene delivery reversed key pathological phenotypes in Mucolipidosis type IV mice, underscoring TRPML-1's critical role in kidney function.

Conclusions: Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV, providing new insights into its pathogenesis and potential therapeutic targets.