|Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking|
|Liu, Maojing1; Chen, Yuqing1; Liang, Yu1; Liu, Ying1; Wang, Suxia1,2; Hou, Ping1; Zhang, Hong1; Zhao, Minghui1|
|关键词||Umod Familial Juvenile Hyperuricemic Nephropathy Uromodulin Tamm-horsfall Protein Fjhn|
|WOS标题词||Science & Technology|
|类目[WOS]||Genetics & Heredity|
|研究领域[WOS]||Genetics & Heredity|
|关键词[WOS]||TAMM-HORSFALL GLYCOPROTEIN ; UNFOLDED PROTEIN RESPONSE ; ENDOPLASMIC-RETICULUM ; GENE ; IDENTIFICATION ; EXPRESSION ; SECRETION ; DISEASE ; BIOLOGY ; CLUSTER|
Background: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder characterized by hyperuricemia and progressive chronic kidney disease. Uromodulin gene (UMOD) mutations, leading to abnormalities of uromodulin intracellular trafficking contribute to the progress of the disease.
Methods: We did UMOD screening in three Chinese FJHN families. We thus constructed mutant uromodulin express plasmids by site-mutagenesis from wild type uromodulin vector and transfected them into HEK293 (human embryonic kidney) cells. And then we detected uromodulin expression by western blot and observed intracellular distribution by immunofluorescence.
Results: We found three heterozygous mutations. Mutation Val109Glu (c.326T/A; p.Val109Glu) and mutation Pro236Gln (c.707C/A; p.Pro236GIn) were newly indentified mutations in two distinct families (family F1 and family F3). Another previously reported UMOD mutation Cys248Trp (c744C/G; p.Cys248Trp) was detected in family F2. Phenotypes varied both within the same family and between different families. Uromodulin expression is abnormal in the patient biopsy. Functional analysis of mutation showed that mutant types of uromodulin were secreted into the supernatant medium much less when compared with wild type. In mutant type uromodulin transfected cells, intracellular uromodulin localized less in the Golgi apparatus and more in endoplasmic reticulum(ER).
Conclusions: Our results suggested that the novel uromodulin mutations found in the Chinese families lead to misfolded protein, which was retained in the endoplasmic reticulum, finally contributed to the phenotype of FJHN. (C) 2013 Elsevier B.V. All rights reserved.
|资助机构||National Natural Science Foundation of China|
|作者单位||1.Peking Univ, Key Lab Chron Kidney Dis Prevent & Treatment, Key Lab Renal Dis,Hosp 1,Minist Educ, Renal Div,Dept Med,Inst Nephrol,Minist Hlth China, Beijing 100871, Peoples R China|
2.Peking Univ, Lab Electron Microscopy, Hosp 1, Beijing 100034, Peoples R China
|Liu, Maojing,Chen, Yuqing,Liang, Yu,et al. Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking[J]. GENE,2013,531(2):363-369.|
|APA||Liu, Maojing.,Chen, Yuqing.,Liang, Yu.,Liu, Ying.,Wang, Suxia.,...&Zhao, Minghui.(2013).Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking.GENE,531(2),363-369.|
|MLA||Liu, Maojing,et al."Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking".GENE 531.2(2013):363-369.|