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NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout

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机构： [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.

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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.© 2024. The Author(s).

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大类 | 1 区生物学

小类 | 2 区细胞生物学

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第一作者机构： [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.

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