A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal.
A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal.
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多发性骨结合综合征的一种新亚型是由 GDF6 突变引起的，该突变降低了其对 Noggin 的敏感性并增强了其作为 BMP 信号的效力
DOI：
10.1002/jbmr.2761
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Shen Y
中科院分区：
文献类型：
--
作者：
Wang J;Yu T;Wang Z;Ohte S;Yao RE;Zheng Z;Geng J;Cai H;Ge Y;Li Y;Xu Y;Zhang Q;Gusella JF;Fu Q;Pregizer S;Rosen V;Shen Y
生长和分化因子 (GDF) 是 BMP 家族中的分泌信号分子，在小鼠和人类骨骼发育过程中的关节形态发生中发挥关键作用。利用从一个六代中国家庭获得的遗传数据，我们鉴定了 GDF6 (NP_001001557.1; p.Y444N) 中的一个错义变异，它与一种新的常染色体显性联生 (SYNS) 表型完全分离，我们将其命名为 SYNS4。受影响的个体在出生时表现出双侧手腕和脚踝畸形，并在 40 岁后出现进行性传导性耳聋。我们发现，Y444N 变体影响 GDF6 高度保守的残基，该残基对于 GDF6 与其受体和 BMP 拮抗剂 NOG 的结合至关重要，并表明与野生型 GDF6 相比，这种突变体 GDF6 是经典 BMP 信号通路的更有效的刺激剂。此外，我们确定突变体 GDF6 表现出的增强的 BMP 活性可归因于对 NOG 介导的拮抗作用的抵抗。总的来说，我们的研究结果表明，GDF6 功能获得性突变导致的 BMP 信号传导增加是 SYNS4 患者关节形成丧失和严重功能障碍的原因。更广泛地说，我们的研究强调了正确的关节形态发生所需的 BMP 信号传导的微妙平衡，并强化了 BMP 信号传导在骨骼发育中的关键作用。
Growth and differentiation factors (GDFs) are secreted signaling molecules within the BMP family that have critical roles in joint morphogenesis during skeletal development in mice and humans. Using genetic data obtained from a six-generation Chinese family, we identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4. Affected individuals display bilateral wrist and ankle deformities at birth and progressive conductive deafness after age 40 years. We find that the Y444N variant affects a highly conserved residue of GDF6 in a region critical for binding of GDF6 to its receptor(s) and to the BMP antagonist NOG, and show that this mutant GDF6 is a more potent stimulator of the canonical BMP signaling pathway compared with wild-type GDF6. Further, we determine that the enhanced BMP activity exhibited by mutant GDF6 is attributable to resistance to NOG-mediated antagonism. Collectively, our findings indicate that increased BMP signaling owing to a GDF6 gain-of-function mutation is responsible for loss of joint formation and profound functional impairment in patients with SYNS4. More broadly, our study highlights the delicate balance of BMP signaling required for proper joint morphogenesis and reinforces the critical role of BMP signaling in skeletal development.