Genome mining yields new disease-associated ROMK variants with distinct defects.

Area of Science:

• Molecular biology and genetics
• Renal physiology
• Computational biology

Background:

• Bartter syndrome is a rare genetic kidney disorder impairing electrolyte reabsorption, potentially fatal if untreated.
• Bartter syndrome type II stems from mutations in the KCNJ1 gene, encoding the renal outer medullary potassium channel (ROMK).
• Many KCNJ1 mutations lead to misfolded ROMK protein, targeted for degradation, but most defects remain uncharacterized.

Conclusions:

• Developed and validated a computational and experimental pipeline to discover disease-causing mutations in KCNJ1 and potentially other potassium channels.
• Characterized specific ROMK mutations, revealing mechanisms of protein destabilization, ERAD targeting, and functional impairment.
• Enhanced understanding of ROMK structure-function relationships, paving the way for future therapeutic strategies for Bartter syndrome.