Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B
Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B
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DOI：
10.1038/73495
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发表时间：
2000-03-01
期刊：
影响因子：
30.8
通讯作者：
Wilkie, AOM
中科院分区：
文献类型：
--
作者：
Oldridge, M;Fortuna, AM;Wilkie, AOM
遗传性肢体畸形为鉴定参与肢体发育的基因提供了宝贵的资源（1，2）。短指（趾）B型（BDB）是一种常染色体显性遗传病，是最严重的短指（趾）畸形（3），其特征为手指和脚趾末端缺失。在典型的BDB形式中，拇指和大脚趾被保留下来，有时会扩大或部分重复（4-8）。BDB 1基因座先前定位在染色体9 q22上7.5 cM的区间内（参考文献9，10）。在此，我们描述了三个不相关的BDB 1家族中编码孤儿受体酪氨酸激酶ROR 2的ROR 2突变（参考文献11）。我们确定了不同的杂合突变（2无义，1移码）内的943个氨基酸的蛋白质的7个氨基酸的片段，所有这些预测截断的细胞内部分的蛋白质后立即酪氨酸激酶结构域。这些突变的局部性质表明它们赋予特定的功能增益。我们通过证明两名9 q22缺失（包括ROR 2）杂合子患者未表现出BDB，获得了进一步的证据。小鼠直系同源物Ror 2在肢体发育早期的表达表明BDB是骨骼模式的主要缺陷。
Inherited limb malformations provide a valuable resource for the identification of genes involved in limb development(1,2). Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies(3) and characterized by terminal deficiency of the fingers and toes. In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication(4-8). The BDB1 locus was previously mapped to chromosome 9q22 within an interval of 7.5 cM (refs 9, 10). Here we describe mutations in ROR2, which encodes the orphan receptor tyrosine kinase ROR2 (ref. 11), in three unrelated families with BDB1. We identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino-acid segment of the 943-amino-acid protein, all of which predict truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggests that they confer a specific gain of function. We obtained further evidence for this by demonstrating that two patients heterozygous for 9q22 deletions including ROR2 do not exhibit BDB. Expression of the mouse orthologue, Ror2, early in limb development indicates that BDB arises as a primary defect of skeletal patterning.