From tall to short: The role of TGFβ signaling in growth and its disorders
From tall to short: The role of TGFβ signaling in growth and its disorders
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DOI：
10.1002/ajmg.c.31337
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发表时间：
2012-08-15
影响因子：
3.1
通讯作者：
Cormier-Daire, Valerie
中科院分区：
文献类型：
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作者：
Le Goff, Carine;Cormier-Daire, Valerie
肢端发育不良组的特征是身材矮小，手脚短小，关节僵硬，肌肉发达。现在可以将四种疾病归因于该组，即WeillMarchesani综合征（WMS）、胶状发育不良（GD）、肢端发育不良（AD）和Myhre综合征（MS）。虽然非常相似，但它们可以通过微妙的临床特征和模式遗传来区分。WMS以微球形晶状体脱位为特征，具有常染色体显性或隐性遗传方式。GD是较严重的一种，伴有进行性心脏瓣膜增厚、气管狭窄、支气管肺功能不全，常导致早期死亡。AD具有常染色体显性遗传模式，独特的面部和骨骼特征（声音嘶哑和股骨头内切迹）。最后，多发性硬化症是散发性的，其特征是多颌畸形、耳聋、发育迟缓、颅骨增厚和椎弓根短而大的大椎骨。我们首先在显性形式的WMS中鉴定了原纤蛋白-1（FBN 1）的突变，然后在隐性形式的WMS中鉴定了具有血栓蛋白1型重复序列10的解聚素样金属蛋白酶结构域（ADAMTS 10）的突变。ADAMTS 10的功能尚不清楚，但这些发现支持ADAMTS 10和FBN 1之间的直接相互作用。然后，我们鉴定了GD隐性形式中ADAMTSL 2的突变以及GD显性形式和AD中FBN 1的突变热点（外显子4142，编码FBN 1的TGF β结合蛋白样结构域5（TB 5））。ADAMTSL 2的功能尚不清楚。使用酵母双杂交筛选，我们确定了潜在的转化生长因子β（TGF β）结合蛋白1作为ADAMTSL 2的合作伙伴。我们发现FBN 1或ADAMTSL 2突变患者的成纤维细胞培养基中活性TGF β水平增加，磷酸化SMAD 2水平增强，这使我们能够得出结论，GD和AD中的TGF β信号增强。最后，ADAMTSL 2和FBN 1之间的直接相互作用得到证实，表明FBN 1/ADAMTSL 2相互关系失调是身材矮小表型的潜在机制。在MS先证者中使用外显子组测序，我们鉴定了从头SMAD 4错义突变，全部涉及MH 2结构域中500位的异亮氨酸残基。在MS成纤维细胞中，我们发现SMAD 4的泛素化水平降低，SMAD 4水平增加，支持SMAD 4蛋白的稳定。功能性SMAD 4是通过与磷酸化SMAD 2/3和SMAD 1/5/8的寡聚化进行典型信号转导所必需的。因此，我们研究了突变SMAD复合物的核定位，发现复合物易位到细胞核。我们最终观察到下游TGF β靶基因的表达减少，支持MS中TGF β驱动的转录控制受损。我们的研究结果支持身材矮小表型与TGF β信号传导之间的直接联系。然而，马凡氏表型中TGF β信号增强的发现支持了调节TGF β作用的未知机制的存在。(C)2012 Wiley Periodicals，Inc.
The acromelic dysplasia group is characterized by short stature, short hands and feet, stiff joint, and muscular build. Four disorders can now be ascribed to this group, namely WeillMarchesani syndrome (WMS), geleophysic dysplasia (GD), acromicric dysplasia (AD), and Myhre syndrome (MS). Although closely similar, they can be distinguished by subtle clinical features and their pattern inheritance. WMS is characterized by the presence of dislocation of microspherophakia and has autosomal dominant or recessive mode of inheritance. GD is the more severe one, with a progressive cardiac valvular thickening, tracheal stenosis, bronchopulmonary insufficiency, often leading to an early death. AD has an autosomal dominant mode of inheritance, distinct facial and skeleton features (a hoarse voice and internal notch of the femoral head). Finally, MS is sporadic, characterized by prognathism, deafness, developmental delay, thickened calvarium, and large vertebrae with short and large pedicles. We first identified mutations in Fibrillin-1 (FBN1) in the dominant form of WMS and then mutations in A Disintegrin-like And Metalloproteinase domain with ThromboSpondin type 1 repeats 10 (ADAMTS10) in the recessive form of WMS. The function of ADAMTS10 is unknown but these findings support a direct interaction between ADAMTS10 and FBN1. We then identified mutations in ADAMTSL2 in the recessive form of GD and a hotspot of mutations in FBN1 in the dominant form of GD and in AD (exon 4142, encoding TGF beta binding protein-like domain 5 (TB5) of FBN1). The function of ADAMTSL2 is unknown. Using a yeast double hybrid screen, we identified latent transforming growth factor-beta (TGF beta) binding protein 1 as a partner of ADAMTSL2. We found an increased level of active TGF beta in the fibroblast medium from patients with FBN1 or ADAMTSL2 mutations and an enhanced phosphorylated SMAD2 level, allowing us to conclude at an enhanced TGF beta signaling in GD and AD. Finally, a direct interaction between ADAMTSL2 and FBN1 was demonstrated suggesting a dysregulation of FBN1/ADAMTSL2 interrelationship as the underlying mechanism of the short stature phenotypes. Using exome sequencing in MS probands, we identified de novo SMAD4 missense mutations, all involving isoleucine residue at position 500, in the MH2 domain. In MS fibroblasts, we found decreased ubiquitination level of SMAD4 and increased level of SMAD4 supporting a stabilization of SMAD4 protein. Functional SMAD4 is required for canonical signal transduction through the oligomerization with phosphorylated SMAD2/3 and SMAD1/5/8. We therefore studied the nuclear localization of mutant SMAD complexes and found that the complexes translocate to the nucleus. We finally observed a decreased expression of downstream TGF beta target genes supporting impaired TGF beta driven transcriptional control in MS. Our findings support a direct link between the short stature phenotypes and the TGF beta signaling. However, the finding of enhanced TGF beta signaling in Marfan phenotypes supports the existence of yet unknown mechanisms regulating TGF beta action. (C) 2012 Wiley Periodicals, Inc.