Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.
Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.
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DOI：
10.1084/jem.20080990
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发表时间：
2008-11-24
期刊：
影响因子：
--
通讯作者：
Trapnell BC
中科院分区：
文献类型：
--
作者：
Suzuki T;Sakagami T;Rubin BK;Nogee LM;Wood RE;Zimmerman SL;Smolarek T;Dishop MK;Wert SE;Whitsett JA;Grabowski G;Carey BC;Stevens C;van der Loo JC;Trapnell BC
原发性肺泡蛋白沉积症(PAP)是一种罕见的综合征，其特征是肺内表面活性物质积聚，根据对转基因小鼠的研究，推测这是由粒细胞/巨噬细胞集落刺激因子(GM-CSF)信号中断所介导的。GM-CSF的作用是通过由GM-CSF结合亚基(GM-CSF-Rα)和非结合亲和力增强亚基(GM-CSF-Rβ)组成的异源受体介导的。我们描述了两个6岁和8岁的姐妹的阵发性肺炎、发育不全和GM-CSF水平升高，并伴有GM-CSF-Rα编码等位基因(CSF2RA)的异常。一个是包含CSF2RA的一条母体X染色体的假常染色体区域的1.6-Mb缺失。另一种是编码G174R替换的父系X染色体等位基因的点突变，改变了细胞因子结合域中的N-连接糖基化位点和GM-CSF-Rα的糖基化，严重降低了原代髓系细胞的GM-CSF结合、受体信号和GM-CSF依赖的功能。将克隆的cDNAs导入细胞，在生理浓度的GM-CSF中复制了信号缺陷。有趣的是，在高GM-CSF浓度下，信号部分被挽救，从而为这些儿童的疾病缓慢发展提供了一个分子解释。这些结果证实了GM-CSF信号对人类表面活性物质的动态平衡至关重要，并证明CSF2RA的突变导致家族性PAP。
Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Rα) and nonbinding affinity-enhancing (GM-CSF-Rβ) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Rα–encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Rα, severely reducing GM-CSF binding, receptor signaling, and GM-CSF–dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.
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DOI：
10.1164/ajrccm.162.2.9910032
发表时间：
2000-08-01
影响因子：
24.7
作者：
Kitamura, T;Uchida, K;Nakata, K
通讯作者：
Nakata, K
影响因子：
32.4
作者：
Shibata, Y;Berclaz, PY;Trapnell, BC
通讯作者：
Trapnell, BC
DOI：
10.1073/pnas.92.21.9565
发表时间：
1995-10-10
影响因子：
11.1
作者：
ROBB, L;DRINKWATER, CC;BEGLEY, CG
通讯作者：
BEGLEY, CG
影响因子：
4.8
作者：
DING, DXH;VERA, JC;GOLDE, DW
通讯作者：
GOLDE, DW
影响因子：
56.9
作者：
DRANOFF, G;CRAWFORD, AD;MULLIGAN, RC
通讯作者：
MULLIGAN, RC