Abnormal trafficking of endogenously expressed BMPR2 mutant allelic products in patients with heritable pulmonary arterial hypertension.
Abnormal trafficking of endogenously expressed BMPR2 mutant allelic products in patients with heritable pulmonary arterial hypertension.
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DOI：
10.1371/journal.pone.0080319
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
de Caestecker M
中科院分区：
文献类型：
--
作者：
Frump AL;Lowery JW;Hamid R;Austin ED;de Caestecker M
在遗传性肺动脉高压 (HPAH) 患者中，已发现 2 型 BMP 受体基因 BMPR2 存在 200 多个杂合突变。 BMPR2 突变绕过无义介导的 mRNA 衰减（NMD 阴性突变）的患者会出现更严重的临床结果。这些突变占 HPAH 突变的 40%，预计会表达 BMPR2 突变产物。然而，内源性 NMD 阴性 BMPR2 突变体产物的表达及其对蛋白质运输和信号传导功能的影响从未被描述过。在这里，我们描述了 HPAH 相关 NMD 阴性 BMPR2 突变的表达和运输，该突变导致 HPAH 患者来源的淋巴细胞和携带相同外显子 2 框内删除的小鼠（Bmpr2 ΔEx2/+ 小鼠）的肺内皮细胞 (PEC) 中 BMPR2 EXON2 (BMPR2ΔEx2) 框内删除。内源性BMPR2ΔEx2突变产物不会到达细胞表面并保留在内质网中。此外，化学伴侣 4-PBA 和 TUDCA 部分恢复了 PEC 中 Bmpr2ΔEx2 的细胞表面表达，表明突变产物是错误折叠的。我们还表明，来自 Bmpr2 ΔEx2/+ 小鼠的 PEC 在 BMP 诱导的 Smad1/5/8 和 Id1 信号轴中存在缺陷，并且化学伴侣的添加可恢复 Smad1/5/8 靶标 Id1 的表达。这些数据表明内源性 NMD 阴性 BMPRΔEx2 突变体产物得到表达，但具有导致 ER 保留的折叠缺陷。使用化学伴侣部分纠正这种折叠缺陷并恢复有缺陷的 BMP 信号传导表明蛋白质折叠剂可用于治疗这些 NMD 阴性 BMPR2 突变的患者。
More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 ΔEx2/+ mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 ΔEx2/+ mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations.
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影响因子：
37.8
作者：
Hong KH;Lee YJ;Lee E;Park SO;Han C;Beppu H;Li E;Raizada MK;Bloch KD;Oh SP
通讯作者：
Oh SP
影响因子：
8.8
作者：
Cogan, JD;Vnencak-Jones, CL;Loyd, JE
通讯作者：
Loyd, JE
影响因子：
4.6
作者：
Délot, EC;Bahamonde, ME;Lyons, KM
通讯作者：
Lyons, KM
DOI：
10.1152/ajpregu.00866.2009
发表时间：
2010-12-01
影响因子：
2.8
作者：
Lowery, Jonathan W.;Frump, Andrea L.;de Caestecker, Mark P.
通讯作者：
de Caestecker, Mark P.
影响因子：
3.5
作者：
Hamid R;Hedges LK;Austin E;Phillips JA 3rd;Loyd JE;Cogan JD
通讯作者：
Cogan JD