The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene.
The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene.
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DOI：
10.1038/jid.2014.455
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发表时间：
2015-03
影响因子：
6.5
通讯作者：
Blankenhorn, Elizabeth P.
中科院分区：
文献类型：
--
作者：
Long, Kristen B.;Li, Zhenghui;Burgwin, Chelsea M.;Choe, Susanna G.;Martyanov, Viktor;Sassi-Gaha, Sihem;Earl, Josh P.;Eutsey, Rory A.;Ahmed, Azad;Ehrlich, Garth D.;Artlett, Carol M.;Whitfield, Michael L.;Blankenhorn, Elizabeth P.
系统性硬化症 (SSc) 是一种病因不明的多基因自身免疫性疾病，其特征是细胞外基质 (ECM) 蛋白过度积累、血管改变和自身抗体。 SSc 的紧致皮肤 (Tsk)2/+ 小鼠模型表现出与 SSc 相似的迹象，包括紧致皮肤和真皮 ECM 蛋白过度沉积。通过连锁分析，我们将 Tsk2 基因突变定位到 1 号染色体上小于 3 兆碱基的位置。我们对 Tsk2/+ 和野生型同窝小鼠的皮肤转录本进行了 RNA 测序，并对跨越该区间的区域进行了基因组捕获 DNA 测序。 Col3a1的III型前胶原氨基末端前肽段（PIIINP）的一个错义点突变被发现是Tsk2的最佳候选者，因此通过体内和体外遗传互补试验证明这个Col3a1突变就是Tsk2基因。所有先前记录的人类 Col3a1 基因突变都与 Ehlers-Danlos 综合征有关，这是一种导致 III 型胶原蛋白合成缺陷的结缔组织疾病。据我们所知，Tsk2 点突变是第一个有记录的与 Col3a1 相关的功能获得性突变，它会导致纤维化。这一发现提供了对 Tsk2/+ 小鼠皮肤纤维化机制的深入了解。
Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to less than 3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of Col3a1 was found to be the best candidate for Tsk2, so both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice.
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影响因子：
6.5
作者：
Pendergrass, Sarah A.;Lemaire, Raphael;Francis, Ian P.;Mahoney, J. Matthew;Lafyatis, Robert;Whitfield, Michael L.
通讯作者：
Whitfield, Michael L.
影响因子：
6.9
作者：
Sassi-Gaha, Sihem;Loughlin, Danielle T.;Artlett, Carol M.
通讯作者：
Artlett, Carol M.
影响因子：
64.8
作者：
RAMACHANDRAN, GN;KARTHA, G
通讯作者：
KARTHA, G
影响因子：
--
作者：
Christner, PJ;Peters, J;Jimenez, SA
通讯作者：
Jimenez, SA
影响因子：
8.8
作者：
Leistritz, Dru F.;Pepin, Melanie G.;Byers, Peter H.
通讯作者：
Byers, Peter H.