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首页> 外文期刊>Journal of Molecular Biology >Molecular Analysis of Two Novel Missense Mutations in the GDF5 Prorcgion That Reduce Protein Activity and Are Associated with Brachydactyly Type C
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Molecular Analysis of Two Novel Missense Mutations in the GDF5 Prorcgion That Reduce Protein Activity and Are Associated with Brachydactyly Type C

机译：GDF5程序中的两个新型错义突变的分子分析，该突变可降低蛋白质活性并与近距离C型相关。

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摘要

Growth and differentiation factor 5 (GDF5) plays a central role in bone and cartilage development by regulating the proliferation and differentiation of chondrogenic tissue. GDF5 is synthesized as a preproprotein. The biological function of the proregion comprising 354 residues is undefined. We identified two families with a heterozygosity for the novel missense mutations p.T201 P or p.L263P located in the proregion of GDF5. The patients presented with dominant brachydactyly type C characterized by the shortening of skeletal elements in the distal extremities. Both mutations gave rise to decreased biological activity in in vitro analyses. The variants reduced the GDF5-induced activation of SMAD signaling by the GDF5 receptors BMPR1A and BMPR1B. Ectopic expression in micromass cultures yielded relatively low protein levels of the variants and showed diminished chondrogenic activity as compared to wild-type GDF5. Interestingly, stimulation of micromass cells with recombinant human proGDF5~(T201p) and proGDF5~(L263P) revealed their reduced chondrogenic potential compared to the wild-type protein. Limited proteolysis of the mutant recombinant proproteins resulted in a fragment pattern profoundly different from wild-type proGDFS. Modeling of a part of the GDF5 proregion into the known three-dimensional structure of TGFf31 latency-associated peptide revealed that the homologous positions of both mutations are conserved regions that may be important for the folding of the mature protein or the assembly of dimeric protein complexes. We hypothesize that the missense mutations p.T201P and p.L263P interfere with the protein structure and thereby reduce the amount of fully processed, biologically active GDF5, finally causing the clinical loss of function phenotype.
机译：生长和分化因子5（GDF5）通过调节软骨形成组织的增殖和分化在骨骼和软骨发育中起着核心作用。 GDF5合成为前蛋白。包含354个残基的前区的生物学功能是不确定的。我们确定了两个家族的新错义突变p.T201 P或p.L263P位于GDF5的​​前区具有杂合性。患者表现为显性C型近距离指征，其特征是远端肢体的骨骼元素缩短。在体外分析中，两种突变均导致生物活性降低。该变体减少了GDF5受体BMPR1A和BMPR1B的GDF5诱导的SMAD信号激活。与野生型GDF5相比，微团培养物中的异位表达产生了相对较低的变体蛋白水平，并且软骨生成活性降低。有趣的是，与野生型蛋白相比，重组人proGDF5〜（T201p）和proGDF5〜（L263P）对微团细胞的刺激显示出降低的软骨形成潜能。突变体重组原蛋白的有限蛋白水解导致片段模式与野生型proGDFS截然不同。将GDF5前区的一部分建模为TGFf31潜伏期相关肽的已知三维结构表明，两个突变的同源位置均为保守区，这对于成熟蛋白的折叠或二聚体蛋白复合物的组装可能很重要。我们假设错义突变p.T201P和p.L263P干扰蛋白质结构，从而减少了完全加工的，具有生物活性的GDF5的​​数量，最终导致功能表型的临床丧失。

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