Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1
Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1
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DOI：
10.1038/ng0997-58
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发表时间：
1997-09-01
期刊：
影响因子：
30.8
通讯作者：
Luyten, FP
中科院分区：
文献类型：
--
作者：
Thomas, JT;Kilpatrick, MW;Luyten, FP
软骨发育不良Grebe型（CGT）是一种常染色体隐性遗传疾病的特点是严重的肢体缩短和畸形。我们已经确定了编码骨形态发生蛋白（BMP）样分子，软骨衍生的形态发生蛋白-1（CCR 1 -1）的基因中的致病点突变。该突变取代酪氨酸的第一个高度保守的半胱氨酸残基在成熟的活性结构域的蛋白质，我们证明，突变的结果在蛋白质，不分泌，在体外是无活性的。它通过阻止其他相关BMP家族成员的分泌而产生显性负效应。我们目前的证据表明，这可能会发生通过形成异二聚体。该突变及其提出的作用机制提供了第一个人类遗传学指示，即不同BMP的复合表达模式决定了肢体和手指的形态发生。
Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis. We have identified a causative point mutation in the gene encoding the bone morphogenetic protein (BMP)-like molecule, cartilage-derived morphogenetic protein-1 (CDMP-1). The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein, We demonstrate that the mutation results in a protein that is not secreted and is inactive in vitro. It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers. The mutation and its proposed mechanism of action provide the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis.