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首页> 外文期刊>Human Genetics >Characterization of a novel missense mutation in the prodomain of GDF5, which underlies brachydactyly type C and mild Grebe type chondrodysplasia in a large Pakistani family
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Characterization of a novel missense mutation in the prodomain of GDF5, which underlies brachydactyly type C and mild Grebe type chondrodysplasia in a large Pakistani family

机译：GDF5前域中一个新的错义突变的特征，该突变是巴基斯坦大家庭中近距离C型和轻度Grebe型软骨发育不良的基础

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摘要

All TGF-beta family members have a prodomain that is important for secretion. Lack of secretion of a TGF-beta family member GDF5 is known to underlie some skeletal abnormalities, such as brachydactyly type C that is characterized by a huge and unexplained phenotypic variability. To search for potential phenotypic modifiers regulating secretion of GDF5, we compared cells overexpressing wild type (Wt) GDF5 and GDF5 with a novel mutation in the prodomain identified in a large Pakistani family with Brachydactyly type C and mild Grebe type chondrodyslplasia (c527T>C; p.Leu176Pro). Initial in vitro expression studies revealed that the p.Leu176Pro mutant (Mut) GDF5 was not secreted outside the cells. We subsequently showed that GDF5 was capable of forming a complex with latent transforming growth factor binding proteins, LTBP1 and LTBP2. Furthermore, secretion of LTBP1 and LTBP2 was severely impaired in cells expressing the Mut-GDF5 compared to Wt-GDF5. Finally, we demonstrated that secretion of Wt-GDF5 was inhibited by the Mut-GDF5, but only when LTBP (LTBP1 or LTBP2) was co-expressed. Based on these findings, we suggest a novel model, where the dosage of secretory co-factors or stabilizing proteins like LTBP1 and LTBP2 in the microenvironment may affect the extent of GDF5 secretion and thereby function as modifiers in phenotypes caused by GDF5 mutations.
机译：所有TGF-beta家族成员都有一个对分泌很重要的前结构域。已知缺乏TGF-β家族成员GDF5的​​分泌是某些骨骼异常的基础，例如以巨大且无法解释的表型变异为特征的近距离C型。为了寻找调节GDF5分泌的潜在表型修饰剂，我们将过表达野生型（Wt）GDF5和GDF5的​​细胞与在一个巴基斯坦大家庭中发现的prodomain中的一个新型突变进行了比较，该家族具有Brachydactyly C型和轻度Grebe型软骨发育不良（c527T> C; p.Leu176Pro）。最初的体外表达研究表明，p.Leu176Pro突变体（Mut）GDF5不分泌到细胞外。随后，我们表明GDF5能够与潜在的转化生长因子结合蛋白LTBP1和LTBP2形成复合物。此外，与Wt-GDF5相比，表达Mut-GDF5的​​细胞中LTBP1和LTBP2的分泌严重受损。最后，我们证明了Mut-GDF5抑制了Wt-GDF5的​​分泌，但仅当LTBP（LTBP1或LTBP2）被共表达时才被抑制。基于这些发现，我们提出了一个新的模型，其中微环境中分泌性辅助因子或稳定蛋白（如LTBP1和LTBP2）的剂量可能会影响GDF5分泌的程度，从而在GDF5突变引起的表型中起修饰作用。

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