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Familial juvenile hyperuricemia nephropathy (FJHN), an autosomal dominant disorder, is caused by mutations in the UMOD gene, which e n c o d e s U r o m o d u l i n , a glycosylphosphatidylinositol-anchored protein that is expressed in the thick ascending limb of the loop of Henle and excreted in the urine. Although uromodulin is the most abundant protein secreted in urine, its physiological role remains unc lear . FJHN symptoms are charac ter i zed by a l t era t i on o f ur inary concentrating ability, tubulo-interstitial fibrosis hyperuricemia and renal cysts at the corticomedullary junction. We recently reported a patients who carried a novel UMOD mutation of G335A(Cys112Tyr:C112Y), associated with a strong familial history of both gout and renal failure. To study the stability of mumant and its effect on the cellular apoptosis, we examined the function of wild-type and mutant uromodulin in the transfected HEK293 cells. The cytosolic and secre ted pro te in l eve l s o f C112Y were significantly decreased in than those of WT with their marked ubiquitination. The half life of C112Y was significantly decreased than that of WT, which was normalized by a proteasome inhibitor associated with increased in Hsp70. The signal of C112Y was significantly decreased in ER and Golgi apparatus with reduced expression at the plasma than WT. The expression of C112Y significantly increased the cellular apoptosis determined by Anexin Vstaining and flow cytometry. Thus,C112Y mutan t showed impa i r ed i n t r ace l l u l a r maturation and trafficking to induce the cellular apoptosis, which may cause the phenotype of FJHN. Sulistiyati Bayu Utami Udin Bahrudin 1) Peili Li 水田栄之助 浜田 紀宏 加藤 雅彦 山本 康孝 荻野 和秀 宗村 千潮 細山田 真 吉田 明雄 太田原 顕 谷口 晋一 山本 一博 久留 一郎 Novel Uromodulin Mutation Causing Familial Juvenile Hyperuricemia Nephropathy to Lead Its Impaired Protein Stability and Cellular Apoptosis.