Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia
Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia
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DOI：
10.1038/ng.166
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发表时间：
2008-08-01
期刊：
影响因子：
30.8
通讯作者：
Cohn, Daniel H.
中科院分区：
文献类型：
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作者：
Rock, Matthew J.;Prenen, Jean;Cohn, Daniel H.
短骨嵴髓是一组临床和遗传异质性的骨骼发育不良，其特征为躯干短小、脊柱侧凸和轻度身材矮小（1）。在这里，我们确定了染色体12q24.1-12q24.2上的常染色体显性形式的短肢症的基因座。在遗传间隔中的基因中，我们选择TRPV 4作为候选基因，其编码瞬时受体电位（TRP）香草酸家族的钙渗透性阳离子通道，因为其软骨选择性基因表达模式。在具有该表型的两个家族中，我们发现了TRPV 4中分别编码R616 Q和V620 I取代的点突变。转染的HEK细胞的膜片钳研究表明，两种突变导致功能的显著增加，其特征在于通过机械刺激或花生四烯酸或TRPV 4特异性激动剂4 α-佛波醇12，13-二癸酸酯（4 α PDD）的激动剂刺激增加的组成型活性和升高的通道活化。因此，这项研究定义了一个以前未知的机制，激活钙渗透性TRP离子通道，在骨骼发育不良的发病机制。
The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature(1). Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.