Mutation of the gene encoding fibrillin-2 results in syndactyly in mice
Mutation of the gene encoding fibrillin-2 results in syndactyly in mice
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DOI：
10.1093/hmg/10.8.835
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发表时间：
2001-04-01
影响因子：
3.5
通讯作者：
Dixon, MJ
中科院分区：
文献类型：
--
作者：
Chaudhry, SS;Gazzard, J;Dixon, MJ
原纤蛋白是大的、富含半胱氨酸的糖蛋白，其形成微纤维并在弹性原纤形成中起核心作用。由染色体15q21.1上的FBN 1和染色体5 q23-q31上的FBN 2编码的Fibrillin-1和Fibrillin-2是高度相似的蛋白质。FBN 1和FBN 2突变分别在常染色体显性微纤维病马凡综合征（MFS）和先天性挛缩性蛛网膜下腔指（CCA）中的发现，突出了它们在弹性纤维的发育和稳态中的重要作用。MFS的特征在于心血管、骨骼和眼部异常，CCA的特征在于长、薄、弯曲的手指、皱巴巴的耳朵和轻度关节挛缩，尽管突变在整个FBN 1中出现，但外显子24-32内的那些聚集与最严重形式的MFS（所谓的新生儿MFS）相关。CCA中描述的所有突变都发生在FBN 2的“新生儿区域”中。MFS和CCA都被认为是通过显性负性机制出现的。对小鼠突变的分析表明，Escherapin-1微纤维主要参与组织稳态而不是弹性基质组装。在当前的研究中，我们已经使用位置候选方法分析了经典的小鼠突变体shaker-with-syndactylism，并证明了Fbn 2的“新生儿区域”之外的功能丧失突变导致小鼠的并指畸形。这些结果表明，与CCA不同的表型可能导致人作为FSN 2的“新生儿区域”之外的突变的结果，
Fibrillins are large, cysteine-rich glycoproteins that form microfibrils and play a central role in elastic fibrillogenesis. Fibrillin-1 and fibrillin-2, encoded by FBN1 on chromosome 15q21.1 and FBN2 on chromosome 5q23-q31, are highly similar proteins. The finding of mutations in FBN1 and FBN2 in the autosomal dominant microfibrillopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), respectively, has highlighted their essential role in the development and homeostasis of elastic fibres, MFS is characterized by cardiovascular, skeletal and ocular abnormalities, and CCA by long, thin, flexed digits, crumpled ears and mild joint contractures, Although mutations arise throughout FBN1, those clustering within exons 24-32 are associated with the most severe form of MFS, so-called neonatal MFS, All the mutations described in CCA occur in the 'neonatal region' of FBN2, Both MFS and CCA are thought to arise via a dominant negative mechanism. The analysis of mouse mutations has demonstrated that fibrillin-1 microfibrils are mainly engaged in tissue homeostasis rather than elastic matrix assembly. In the current investigation, we have analysed the classical mouse mutant shaker-with-syndactylism using a positional candidate approach and demonstrated that loss-of-function mutations outside the 'neonatal region' of Fbn2 cause syndactyly in mice, These results suggest that phenotypes distinct from CCA may result in man as a consequence of mutations outside the 'neonatal region' of FSN2,