Chen Huan-Da, Yu Chih-Chuan, Yang I-Hsiao, Hung Chi-Chih, Kuo Mei-Chuan, Tarng Der-Cherng, Chang Jer-Ming, Hwang Daw-Yang
Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807377, Taiwan.
National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan.
Biomedicines. 2022 Sep 13;10(9):2265. doi: 10.3390/biomedicines10092265.
UMOD is the first identified and the most commonly mutated gene that causes autosomal dominant tubulointerstitial kidney disease (ADTKD). Recent studies have shown that ADTKD-UMOD is a relatively common cause of chronic kidney disease (CKD). However, the status of ADTKD-UMOD in Taiwan remains unknown. In this study, we identified three heterozygous UMOD missense variants, c.121T > C (p.Cys41Arg), c.179G > A (p.Gly60Asp), and c.817G > T (p.Val273Phe), in a total of 221 selected CKD families (1.36%). Two of these missense variants, p.Cys41Arg and p.Gly60Asp, have not been reported previously. In vitro studies showed that both uromodulin variants have defects in cell membrane trafficking and excretion to the culture medium. The structure model predicted altered disulfide bond formation in both variants, but only p.Gly60Asp was predicted to cause protein destabilization. Our findings extend the mutation spectrum and indicate that the ADTKD-UMOD contributed to a small but significant cause of CKD in the Taiwanese population.
UMOD是首个被鉴定出且最常发生突变的导致常染色体显性遗传性肾小管间质性肾病（ADTKD）的基因。近期研究表明，ADTKD-UMOD是慢性肾脏病（CKD）相对常见的病因。然而，ADTKD-UMOD在台湾地区的情况仍不明确。在本研究中，我们在总共221个选定的CKD家族中（占1.36%）鉴定出三个杂合的UMOD错义变异，即c.121T>C（p.Cys41Arg）、c.179G>A（p.Gly60Asp）和c.817G>T（p.Val273Phe）。其中两个错义变异，p.Cys41Arg和p.Gly60Asp，此前尚未见报道。体外研究表明，这两种尿调节蛋白变异体在细胞膜转运和向培养基排泄方面均存在缺陷。结构模型预测这两种变异体中均有二硫键形成改变，但仅p.Gly60Asp被预测会导致蛋白质不稳定。我们的研究结果扩展了突变谱，并表明ADTKD-UMOD是台湾人群中CKD的一个虽小但重要的病因。
