Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2
Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2
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DOI：
10.1038/78107
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发表时间：
2000-08-01
期刊：
影响因子：
30.8
通讯作者：
Jeffery, S
中科院分区：
文献类型：
--
作者：
Afzal, AR;Rajab, A;Jeffery, S
常染色体隐性形式的Robinow综合征（RRS; MIM 268310）是一种严重的骨骼发育不良，伴全身性肢体骨缩短、脊柱节段性缺损、短指畸形和畸形面部外观（1-3）。我们之前将RRS中突变的基因定位到染色体9q22上（参考文献4），该区域与常染色体显性短指畸形B型的位点重叠（参考文献5,6）。最近发现，编码孤儿受体酪氨酸激酶的ROR2基因在短指型B （BDB1；文献7）中发生突变，而在小鼠中纯合的lacZ和/或新插入ROR2（文献8.9）使该基因成为RRS的候选基因。在这里，我们报告了来自3个不相关的近亲家庭的受影响个体的ROR2细胞内和细胞外结构域的纯合错义突变，以及来自阿曼7个家庭的14名患者的酪氨酸激酶结构域和所有随后的3'区域的无义突变。这些突变的性质表明，RRS是由ROR2活性的丧失引起的。在三个不同结构域（包含Frizzled-like， kringle和酪氨酸激酶基序）的突变鉴定表明，这些都是ROR2功能所必需的。
The autosomal recessive form of Robinow syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance(1-3). We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5,6). The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8.9) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.