Screening and function discussion of a hereditary renal tubular acidosis family pathogenic gene.,Cell Death & Disease

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Screening and function discussion of a hereditary renal tubular acidosis family pathogenic gene.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-03-02 , DOI: 10.1038/s41419-020-2354-y
Li Chen _{1,

2} , Han-Lu Wang ₁ , Yao-Bin Zhu ₃ , Zhao Jin ₁ , Jian-Bin Huang ₁ , Xin-Fu Lin _{1,

4} , Jie-Wei Luo _{1,

2} , Zhu-Ting Fang _{1,

5}

Affiliation

Hereditary distal renal tubular acidosis (dRTA) is a rare disease of H+ excretion defect of α-intercalated cells in renal collecting duct, caused by decreased V-ATPase function due to mutations in the ATP6V1B1 or ATP6V0A4 genes. In the present study, a genetic family with 5 members of the complete dRTA phenotype were found with distal tubule H+ secretion disorder, hypokalemia, osteoporosis, and kidney stones. A variant NM_020632.2:c.1631C > T (p.Ser544Leu) in exon 16 on an ATP6V0A4 gene associated with dRTA was detected by next generation sequencing target region capture technique and verified by Sanger sequencing, which suggested that except for one of the patients who did not receive the test, the other four patients all carried the p.S544L heterozygote. In transfected HEK293T cells, cells carrying p.S544L-mut showed early weaker ATPase activity and a slower Phi recovery rate after rapid acidification. By immunofluorescence localization, it was observed that the expression level of p.S544L-mut on the cell membrane increased and the distribution was uneven. Co-immunoprecipitation showed the a4 subunit of ATP6V0A4/p.S544L-mut could not bind to the B1 subunit, which might affect the correct assembly of V-ATPase. The present study of dRTA family suggests that the p.S544L variant may be inherited in a dominant manner.

中文翻译：

遗传性肾小管性酸中毒家族致病基因的筛选和功能讨论。

遗传性远端肾小管性酸中毒（dRTA）是一种罕见的疾病，是由于ATP6V1B1或ATP6V0A4基因的突变导致V-ATPase功能下降，导致肾脏收集管中的α插入细胞H +排泄缺陷。在本研究中，发现具有5个完整dRTA表型成员的遗传家族患有远端肾小管H +分泌障碍，低钾血症，骨质疏松和肾结石。通过下一代测序目标区域捕获技术检测了与dRTA相关的ATP6V0A4基因外显子16的变体NM_020632.2：c.1631C> T（p.Ser544Leu），并通过Sanger测序进行了验证，这表明除了没有接受检查的患者，其他四名患者均携带p.S544L杂合子。在转染的HEK293T细胞中，携带p的细胞。S544L-mut在快速酸化后显示出较弱的ATPase活性和较慢的Phi回收率。通过免疫荧光定位，观察到p.S544L-mut在细胞膜上的表达水平增加并且分布不均匀。免疫共沉淀显示ATP6V0A4 / p的a4亚基不能与B1亚基结合，这可能影响V-ATPase的正确装配。dRTA家族的当前研究表明，p.S544L变体可能以显性方式遗传。这可能会影响V-ATPase的正确组装。dRTA家族的当前研究表明，p.S544L变体可能以显性方式遗传。这可能会影响V-ATPase的正确组装。dRTA家族的当前研究表明，p.S544L变体可能以显性方式遗传。

更新日期：2020-03-02

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