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NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout
Jingwei Chi1,2,3, Ying Chen1, Changgui Li1,4
1Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Cell Discovery
|October 21, 2024
Summary
A rare NUMB gene variant causes gout by disrupting uric acid excretion. This discovery reveals a new mechanism for hyperuricemia and identifies a potential therapeutic target for gout.
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- Hyperuricemia, a precursor to gout, results from impaired uric acid excretion or overproduction.
- The molecular basis for defective renal uric acid excretion is not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms of defective uric acid excretion.
- To identify genetic factors contributing to hereditary gout.
Main Methods:
- Genome-wide sequencing to identify genetic variants in a gout family.
- Functional studies in renal tubular epithelial cells (RTECs) to assess the role of the NUMB gene.
- Generation and analysis of a NUMB R630H knock-in mouse model.
Main Results:
- A novel, dysfunctional missense variant (NUMBR630H) in the NUMB gene was identified in a human gout family.
- NUMB interacts with the uric acid transporter ABCG2, promoting its apical localization in RTECs.
- Loss-of-function of NUMB leads to ABCG2 mislocalization and defective uric acid excretion.
- NUMBR630H knock-in mice exhibit hyperuricemia and reduced uric acid excretion, mirroring human gout phenotypes.
Conclusions:
- A novel NUMB-mediated pathway for uric acid excretion has been uncovered.
- A functional NUMB missense variant contributes to hyperuricemia and gout in humans.
- The NUMB-ABCG2 interaction is critical for proper uric acid transport in the kidneys.
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