NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout

Cell Discov. 2024 Oct 22;10(1):106. doi: 10.1038/s41421-024-00708-6.

Jingwei Chi ^# ¹ ² ³, Ying Chen ^# ¹, Changgui Li ¹ ⁴, Shiguo Liu ⁵ ⁶, Kui Che ¹ ², Zili Kong ¹, Ziheng Guo ⁷, Yanchen Chu ⁸, Yajing Huang ¹, Libo Yang ⁹, Cunwei Sun ¹, Yunyang Wang ¹, Wenshan Lv ¹, Qing Zhang ¹, Hui Guo ¹, Han Zhao ¹⁰, Zhitao Yang ¹¹, Lili Xu ¹, Ping Wang ¹, Bingzi Dong ¹, Jianxia Hu ¹, Shihai Liu ², Fei Wang ¹, Yanyun Zhao ¹, Mengmeng Qi ¹, Yu Xin ¹, Huiqi Nan ¹, Xiangzhong Zhao ², Wei Zhang ¹, Min Xiao ¹, Ke Si ¹, Yangang Wang ¹², Yihai Cao ¹³

Affiliations

1 Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
2 Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
3 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
4 Institute of Metabolic Diseases, Qingdao University, Qingdao, Shandong, China.
5 Department of Medical Genetics, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
6 Prenatal Diagnosis Center, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
7 Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
8 Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
9 Department of Endocrinology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China.
10 Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
11 Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
12 Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. wangyg@qdu.edu.cn.
13 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden. yihai.cao@ki.se.
# Contributed equally.

PMID: 39433541 DOI: 10.1038/s41421-024-00708-6

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 (NUMB^R630H) 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 NUMB^R630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMB^R630H 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.

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