Transforming growth factor-β (TGF-β) pathway abnormalities in tenascin-X deficiency associated with CAH-X syndrome.
Transforming growth factor-β (TGF-β) pathway abnormalities in tenascin-X deficiency associated with CAH-X syndrome.
复制标题
DOI：
10.1016/j.ejmg.2013.12.004
复制
发表时间：
2014-02
影响因子：
1.9
通讯作者：
McDonnell NB
中科院分区：
文献类型：
--
作者：
Morissette R;Merke DP;McDonnell NB
先天性肾上腺增生症（CAH）伴生腱蛋白X缺乏（CAH-X综合征）患者同时具有内分泌失衡和特征性Ehlers Danlos综合征表型。与其他亚型不同，腱生蛋白-X相关的Ehlers Danlos综合征是由细胞外基质蛋白缺乏引起的，而不是纤维胶原或胶原修饰酶的缺陷，并且对疾病机制的理解有限。我们假设，转化生长因子-β途径失调可能部分导致CAH-X中观察到的结缔组织表型，因为该途径在结缔组织疾病中的已知作用。对来自CAH-X先证者和年龄和性别匹配对照的人皮肤活检的成纤维细胞和直接组织进行筛选，以确定已知在其他遗传性结缔组织疾病中失调的转化生长因子-β生物标志物。在CAH-X成纤维细胞系和真皮组织中，与对照组相比，pSmad 1/5/8显著上调，表明骨形态发生蛋白途径的参与。此外，与对照组相比，CAH-X样本显示成纤维细胞分泌的TGF-β3（一种在继发性腭发育中重要的细胞因子）和血浆TGF-β2（一种参与心脏功能和发育以及腭发生的细胞因子）显著增加。最后，MMP-13，一种在继发性腭形成和组织重塑中重要的基质金属蛋白酶，在CAH-X成纤维细胞和直接组织中显著增加mRNA和蛋白表达。总的来说，这些结果表明，CAH-X综合征患者表现出几种转化生长因子-β生物标志物的表达增加，并提供了这种信号传导途径与腱生蛋白-X缺乏相关的结缔组织发育不良表型之间的新联系。
Patients with congenital adrenal hyperplasia (CAH) with tenascin-X deficiency (CAH-X syndrome) have both endocrine imbalances and characteristic Ehlers Danlos syndrome phenotypes. Unlike other subtypes, tenascin-X-related Ehlers Danlos syndrome is caused by an extracellular matrix protein deficiency rather than a defect in fibrillar collagen or a collagen-modifying enzyme, and the understanding of the disease mechanisms is limited. We hypothesized that transforming growth factor-β pathway dysregulation may, in part, be responsible for connective tissue phenotypes observed in CAH-X, due to this pathway’s known role in connective tissue disorders. Fibroblasts and direct tissue from human skin biopsies from CAH-X probands and age- and sex-matched controls were screened for transforming growth factor-β biomarkers known to be dysregulated in other hereditary disorders of connective tissue. In CAH-X fibroblast lines and dermal tissue, pSmad1/5/8 was significantly upregulated compared to controls, suggesting involvement of the bone morphogenetic protein pathway. Additionally, CAH-X samples compared to controls exhibited significant increases in fibroblast-secreted TGF-β3, a cytokine important in secondary palatal development, and in plasma TGF-β2, a cytokine involved in cardiac function and development, as well as palatogenesis. Finally, MMP-13, a matrix metalloproteinase important in secondary palate formation and tissue remodeling, had significantly increased mRNA and protein expression in CAH-X fibroblasts and direct tissue. Collectively, these results demonstrate that patients with CAH-X syndrome exhibit increased expression of several transforming growth factor-β biomarkers and provide a novel link between this signaling pathway and the connective tissue dysplasia phenotypes associated with tenascin-X deficiency.
登录
查看更多内容
影响因子：
2.5
作者：
Azhar, Mohamad;Brown, Kristen;Gard, Connie;Chen, Hwudaurw;Rajan, Sudarsan;Elliott, David A.;Stevens, Mark V.;Camenisch, Todd D.;Conway, Simon J.;Doetschman, Thomas
通讯作者：
Doetschman, Thomas
DOI：
10.1126/science.1192149
发表时间：
2011-04-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Holm TM;Habashi JP;Doyle JJ;Bedja D;Chen Y;van Erp C;Lindsay ME;Kim D;Schoenhoff F;Cohn RD;Loeys BL;Thomas CJ;Patnaik S;Marugan JJ;Judge DP;Dietz HC
通讯作者：
Dietz HC
影响因子：
2.5
作者：
Azhar, Mohamad;Runyan, Raymond B.;Gard, Connie;Sanford, L. Philip;Miller, Marian L.;Andringa, Anastasia;Pawlowski, Sharon;Rajan, Sudarsan;Doetschman, Thomas
通讯作者：
Doetschman, Thomas
影响因子：
3.3
作者：
Blavier, L;Lazaryev, A;Kaartinen, V
通讯作者：
Kaartinen, V
影响因子：
30.8
作者：
PROETZEL, G;PAWLOWSKI, SA;DOETSCHMAN, T
通讯作者：
DOETSCHMAN, T