In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• The megalin/cubilin/amnionless complex is crucial for reabsorbing albumin and low molecular weight (LMW) proteins in renal proximal tubules (PT).
• Mutations in the LRP2 gene, encoding megalin, result in autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), characterized by LMW proteinuria.
• The precise mechanisms underlying PT dysfunction in DB/FOAR are not fully understood.

Observation:

• A pediatric patient with DB/FOAR presented with growth retardation, proteinuria, myopia, delayed psychomotor development, and sensorineural hearing loss.
• Urinalysis revealed significant albumin and LMW proteinuria, with urinary detection of cubilin and carbonic anhydrase 3 (CA3).
• Electron microscopy of renal biopsy showed underdeveloped PT apical endocytic apparatus, with megalin deficiency and altered cubilin distribution.

Findings:

• Genetic analysis identified two mutations in the LRP2 gene, confirming the diagnosis of DB/FOAR.
• The study demonstrates that functional loss of megalin impairs the reabsorptive capacity of renal proximal tubules.
• Increased urinary excretion of CA3 and cubilin serves as a marker for megalin deficiency-induced PT dysfunction.

Implications:

• This research elucidates the pathophysiology of DB/FOAR, linking LRP2 gene mutations to specific PT defects.
• Understanding megalin's role provides insights into protein handling by the kidney and potential therapeutic targets.
• The findings highlight the diagnostic utility of urinary CA3 and cubilin levels in managing patients with DB/FOAR.