Cell Discovery (Oct 2024)

NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout

  • Jingwei Chi,
  • Ying Chen,
  • Changgui Li,
  • Shiguo Liu,
  • Kui Che,
  • Zili Kong,
  • Ziheng Guo,
  • Yanchen Chu,
  • Yajing Huang,
  • Libo Yang,
  • Cunwei Sun,
  • Yunyang Wang,
  • Wenshan Lv,
  • Qing Zhang,
  • Hui Guo,
  • Han Zhao,
  • Zhitao Yang,
  • Lili Xu,
  • Ping Wang,
  • Bingzi Dong,
  • Jianxia Hu,
  • Shihai Liu,
  • Fei Wang,
  • Yanyun Zhao,
  • Mengmeng Qi,
  • Yu Xin,
  • Huiqi Nan,
  • Xiangzhong Zhao,
  • Wei Zhang,
  • Min Xiao,
  • Ke Si,
  • Yangang Wang,
  • Yihai Cao

DOI
https://doi.org/10.1038/s41421-024-00708-6
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 16

Abstract

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Abstract Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMBR630H) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMBR630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMBR630H knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.