TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV

Area of Science:

• Lysosome biology
• Ion channel function
• Rare genetic diseases

Background:

• Mucolipidosis type IV (MLIV) is a rare lysosomal storage disease caused by loss-of-function mutations in the TRPML-1 channel.
• MLIV is associated with neurological defects, vision loss, and achlorhydria.
• Kidney disease and failure are increasingly recognized in MLIV patients, but underlying mechanisms are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms of kidney dysfunction in MLIV.
• To assess kidney function impairment in MLIV patients and MLIV mouse models.

Main Methods:

• Cross-sectional review of medical records from 21 MLIV patients.
• Phenotypic analysis of kidney tissues from MLIV mice and human kidney cells.
• Immunohistology, cell biology, proteomic analysis of mouse urine, and in vivo kidney filtration measurements.

Main Results:

• Adult MLIV patients exhibited stage 2-3 chronic kidney disease (CKD) with reduced eGFR and proteinuria.
• MLIV mice showed endolysosomal defects, impaired autophagy, and blocked receptor-mediated endocytosis in kidney tubules.
• TRPML-1 gene delivery ameliorated kidney pathology in MLIV mice.

Conclusions:

• TRPML-1 dysfunction is directly linked to kidney disease development in MLIV.
• Endolysosomal defects and impaired endocytosis are key contributors to MLIV nephropathy.
• TRPML-1 plays a critical role in maintaining kidney function.