Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum
Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum
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DOI：
10.1007/s00439-007-0409-0
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发表时间：
2007-11-01
期刊：
影响因子：
5.3
通讯作者：
Afzal, Ali R.
中科院分区：
文献类型：
--
作者：
Ali, Bassam R.;JeVery, Steve;Afzal, Ali R.
ROR2是蛋白质的细胞表面受体酪氨酸激酶（RTK）家族的成员，并且参与骨骼、心血管和生殖系统的发育形态发生。ROR 2突变已显示可引起两种不同的人类疾病，常染色体隐性Robinow综合征和显性遗传短指（趾）畸形B型。隐性形式的Robinow综合征是由功能丧失突变引起的疾病，而短指（趾）畸形B型是显性疾病，可能是由同一基因中的功能获得突变引起的。我们先前已经确定，ROR2中导致Robinow综合征的所有错义突变都保留在内质网中，因此得出结论，它们的功能丧失是由于它们的细胞内运输缺陷。这些突变位于卷曲样富含半胱氨酸结构域和kringle结构域的远端部分。在这里，我们报告了两个新的ROR2卷曲样富含半胱氨酸结构域的突变导致Robinow综合征的鉴定。我们建立了HeLa细胞内质网中的突变蛋白质的保留，因此未能到达质膜。ROR2的胞外卷曲样富含半胱氨酸结构域中Robinow引起的突变的聚集表明，在ROR2从内质网输出到质膜之前，该结构域的正确折叠是严格要求的。
ROR2 is a member of the cell surface receptor tyrosine kinase (RTKs) family of proteins and is involved in the developmental morphogenesis of the skeletal, cardiovascular and genital systems. Mutations in ROR2 have been shown to cause two distinct human disorders, autosomal recessive Robinow syndrome and dominantly inherited Brachydactyly type B. The recessive form of Robinow syndrome is a disorder caused by loss-of-function mutations whereas Brachydactyly type B is a dominant disease and is presumably caused by gain-of-function mutations in the same gene. We have previously established that all the missense mutations causing Robinow syndrome in ROR2 are retained in the endoplasmic reticulum and therefore concluded that their loss of function is due to a defect in their intracellular trafficking. These mutations were in the distal portion of the frizzled-like cysteine rich domain and kringle domain. Here we report the identification of two novel mutations in the frizzled-like cysteine-rich domain of ROR2 causing Robinow syndrome. We establish the retention of the mutated proteins in the endoplasmic reticulum of HeLa cells and therefore failure to reach the plasma membrane. The clustering of Robinow-causing mutations in the extracellular frizzled-like cysteine-rich domain of ROR2 suggests a stringent requirement for the correct folding of this domain prior to export of ROR2 from the endoplasmic reticulum to the plasma membrane.