Temtamy Preaxial Brachydactyly Syndrome Is Caused by Loss-of-Function Mutations in Chondroitin Synthase 1, a Potential Target of BMP Signaling
Temtamy Preaxial Brachydactyly Syndrome Is Caused by Loss-of-Function Mutations in Chondroitin Synthase 1, a Potential Target of BMP Signaling
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DOI：
10.1016/j.ajhg.2010.10.003
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发表时间：
2010-12-10
影响因子：
9.8
通讯作者：
Wollnik, Bernd
中科院分区：
文献类型：
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作者：
Li, Yun;Laue, Kathrin;Wollnik, Bernd
骨形态发生蛋白（BMP）信号的改变导致多种发育缺陷，包括短指和耳聋。在这里，我们确定软骨素合成酶1 （CHSY1）作为BMP效应的潜在介质。我们发现，人类CHSY1功能的丧失会导致常染色体隐性的Temtamy前轴短指综合征（ITBS），主要表现为肢体畸形、身材矮小和听力丧失。在将TITS位点定位到染色体15q26-qterm后，我们在5个近亲TPBS家族中发现了致病突变。在斑马鱼中，反义介导的chsy1敲低会导致多个发育过程中的缺陷，其中一些缺陷也可能是TPBS的病因学原因。在斑马鱼幼体的内耳中，chsy1的表达与BMP抑制剂don相似，并与bmp2b互补。此外，不受限制的Bmp2b信号传导或Dan活性的丧失导致chsy1表达减少，并且在上皮形态发生过程中，出现与chsy1失活时相似的缺陷，这表明Bmp信号传导通过抑制chsy1影响内耳发育。此外，我们在chsy1过表达后获得了惊人相似的斑马鱼表型，这可能解释了为什么在人类中，短指可以由导致BMP信号丢失或获得的突变引起。
Altered Bone Morphogenetic Protein (BMP) signaling leads to multiple developmental defects, including brachydactyly and deafness. Here we identify chondroitin synthase 1 (CHSY1) as a potential mediator of BMP effects. We show that loss of human CHSY1 function causes autosomal-recessive Temtamy preaxial brachydactyly syndrome (ITBS), mainly characterized by limb malformations, short stature, and hearing loss. After mapping the TITS locus to chromosome 15q26-qterm, we identified causative mutations in five consanguineous TPBS families. In zebrafish, antisense-mediated chsy1 knockdown causes defects in multiple developmental processes, some of which are likely to also be causative in the etiology of TPBS. In the inner ears of zebrafish larvae, chsy1 is expressed similarly to the BMP inhibitor don and in a complementary fashion to bmp2b. Furthermore, unrestricted Bmp2b signaling or loss of Dan activity leads to reduced chsy1 expression and, during epithelial morphogenesis, defects similar to those that occur upon Chsy1 inactivation, indicating that Bmp signaling affects inner-ear development by repressing chsy1. In addition, we obtained strikingly similar zebrafish phenotypes after chsy1 overexpression, which might explain why, in humans, brachydactyly can be caused by mutations leading either to loss or to gain of BMP signaling.