ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome.
ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome.
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DOI：
10.1093/hmg/ddy276
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发表时间：
2018-11-01
影响因子：
3.5
通讯作者：
Baldock C
中科院分区：
文献类型：
--
作者：
Mularczyk EJ;Singh M;Godwin ARF;Galli F;Humphreys N;Adamson AD;Mironov A;Cain SA;Sengle G;Boot-Handford RP;Cossu G;Kielty CM;Baldock C
原纤蛋白微纤维是细胞外基质集合体，其形成弹性纤维的模板，赋予血管、皮肤和其他弹性组织可伸展的性质。它们还调节TGF-β超家族的有效生长因子的生物利用度。具有血小板反应蛋白基序的去整合素和金属蛋白酶（ADAMTS）10是微纤维功能中的一个重要因子。ADAMTS 10突变导致Weill-Marchesani综合征（WMS），其特征是身材矮小，眼睛缺陷，肌肉过多和皮肤增厚。尽管它的重要性，有很少的了解ADAMTS 10的作用和它的功能，在微纤维组装的微纤维。我们已经产生了一个ADAMTS 10 WMS小鼠模型，该模型使用了重复的规则间隔的间隔短回文重复序列和CRISPR相关蛋白9（CRISPR-Cas9）来引入在WMS患者中观察到的截短突变。纯合子WMS小鼠较小，长骨较短，发育中的生长板区域受到干扰，细胞增殖发生变化。此外，在眼睛的睫状体中存在异常，具有减少的睫状突起和丰富的微纤维蛋白-2微纤维，这表明发育表达开关的扰动。WMS小鼠骨骼肌质量增加，肌纤维增多，这可能是骨骼肌发生改变的结果。这些结果与显示生长分化因子（GDF 8）和骨形态发生蛋白（BMP）生长因子基因下调的表达数据相关。此外，骨骼肌中的线粒体较大，形状不规则，加上磷酸化p38丝裂原活化蛋白激酶（MAPK）的增加，表明肌肉重塑。我们的数据表明，SMAD 1/5/8减少和p38/MAPK信号增加与ADAMTS 10诱导的WMS有关。该模型将允许进一步研究疾病机制，以促进治疗干预措施的发展。
Fibrillin microfibrils are extracellular matrix assemblies that form the template for elastic fibres, endow blood vessels, skin and other elastic tissues with extensible properties. They also regulate the bioavailability of potent growth factors of the TGF-β superfamily. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)10 is an essential factor in fibrillin microfibril function. Mutations in fibrillin-1 or ADAMTS10 cause Weill–Marchesani syndrome (WMS) characterized by short stature, eye defects, hypermuscularity and thickened skin. Despite its importance, there is poor understanding of the role of ADAMTS10 and its function in fibrillin microfibril assembly. We have generated an ADAMTS10 WMS mouse model using Clustered Regularly Spaced Interspaced Short Palindromic Repeats and CRISPR associated protein 9 (CRISPR-Cas9) to introduce a truncation mutation seen in WMS patients. Homozygous WMS mice are smaller and have shorter long bones with perturbation to the zones of the developing growth plate and changes in cell proliferation. Furthermore, there are abnormalities in the ciliary apparatus of the eye with decreased ciliary processes and abundant fibrillin-2 microfibrils suggesting perturbation of a developmental expression switch. WMS mice have increased skeletal muscle mass and more myofibres, which is likely a consequence of an altered skeletal myogenesis. These results correlated with expression data showing down regulation of Growth differentiation factor (GDF8) and Bone Morphogenetic Protein (BMP) growth factor genes. In addition, the mitochondria in skeletal muscle are larger with irregular shape coupled with increased phospho-p38 mitogen-activated protein kinase (MAPK) suggesting muscle remodelling. Our data indicate that decreased SMAD1/5/8 and increased p38/MAPK signalling are associated with ADAMTS10-induced WMS. This model will allow further studies of the disease mechanism to facilitate the development of therapeutic interventions.
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DOI：
10.1002/ajmg.c.31337
发表时间：
2012-08-15
影响因子：
3.1
作者：
Le Goff, Carine;Cormier-Daire, Valerie
通讯作者：
Cormier-Daire, Valerie
影响因子：
5.5
作者：
McClung, J. M.;Judge, A. R.;Yan, Z.
通讯作者：
Yan, Z.
影响因子：
3.5
作者：
Collin, Gayle B.;Hubmacher, Dirk;Nishina, Patsy M.
通讯作者：
Nishina, Patsy M.
影响因子：
4.8
作者：
Cain, SA;Baldock, C;Kielty, CM
通讯作者：
Kielty, CM
影响因子：
4.5
作者：
Rajpar MH;McDermott B;Kung L;Eardley R;Knowles L;Heeran M;Thornton DJ;Wilson R;Bateman JF;Poulsom R;Arvan P;Kadler KE;Briggs MD;Boot-Handford RP
通讯作者：
Boot-Handford RP