A novel TRPC6 mutation that causes childhood FSGS.
A novel TRPC6 mutation that causes childhood FSGS.
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DOI：
10.1371/journal.pone.0007771
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发表时间：
2009-11-10
期刊：
影响因子：
3.7
通讯作者：
Hildebrandt F
中科院分区：
文献类型：
--
作者：
Heeringa SF;Möller CC;Du J;Yue L;Hinkes B;Chernin G;Vlangos CN;Hoyer PF;Reiser J;Hildebrandt F
TRPC 6编码离子通道的瞬时受体电位（TRP）超家族的成员，是钙渗透性阳离子通道，其介导电容性钙进入细胞。直到今天，TRPC 6中的七种不同突变已被确定为成人常染色体显性局灶节段性肾小球硬化症（FSGS）的原因。在这里，我们报告了一种新的TRPC 6突变，导致早发性FSGS。我们确定了一个家庭，其中疾病与一种新的TRPC 6突变（M132 T）分离，这种突变也影响了早在9岁的儿童个体。从全球550个类固醇耐药肾病综合征（SRNS）家系中选择21个符合常染色体显性遗传模式和活检证实的FSGS家系。与野生型通道相比，突变体TRPC 6通道的全细胞电流记录显示平均外向和内向TRPC 6电流幅度增加3至5倍。M132 T的平均内向钙电流是野生型TRPC 6的10倍。有趣的是，M132 T突变体也缺乏时间依赖性失活。新的双突变体M132 T/N143 S的产生没有进一步增加TRPC 6通道活性。总之，我们的数据表明TRPC 6介导的FSGS也可以在儿童中发现。由M132 T突变体引起的通道电流的大幅增加和受损的通道失活导致了强调通过TRPC 6引导的钙剂量的重要性的侵袭性表型。
TRPC6, encoding a member of the transient receptor potential (TRP) superfamily of ion channels, is a calcium-permeable cation channel, which mediates capacitive calcium entry into the cell. Until today, seven different mutations in TRPC6 have been identified as a cause of autosomal-dominant focal segmental glomerulosclerosis (FSGS) in adults. Here we report a novel TRPC6 mutation that leads to early onset FSGS. We identified one family in whom disease segregated with a novel TRPC6 mutation (M132T), that also affected pediatric individuals as early as nine years of age. Twenty-one pedigrees compatible with an autosomal-dominant mode of inheritance and biopsy-proven FSGS were selected from a worldwide cohort of 550 families with steroid resistant nephrotic syndrome (SRNS). Whole cell current recordings of the mutant TRPC6 channel, compared to the wild-type channel, showed a 3 to 5-fold increase in the average out- and inward TRPC6 current amplitude. The mean inward calcium current of M132T was 10-fold larger than that of wild-type TRPC6. Interestingly, M132T mutants also lacked time-dependent inactivation. Generation of a novel double mutant M132T/N143S did not further augment TRPC6 channel activity. In summary, our data shows that TRPC6 mediated FSGS can also be found in children. The large increase in channel currents and impaired channel inactivation caused by the M132T mutant leads to an aggressive phenotype that underlines the importance of calcium dose channeled through TRPC6.
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