ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation.
ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation.
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DOI：
10.1038/ng.199
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发表时间：
2008-09
期刊：
影响因子：
30.8
通讯作者：
Cormier-Daire, Valerie
中科院分区：
文献类型：
--
作者：
Le Goff, Carine;Morice-Picard, Fanny;Dagoneau, Nathalie;Wang, Lauren W.;Perrot, Claire;Crow, Yanick J.;Bauer, Florence;Flori, Elisabeth;Prost-Squarcioni, Catherine;Krakow, Deborah;Ge, Gaoxiang;Greenspan, Daniel S.;Bonnet, Damien;Le Merrer, Martine;Munnich, Arnold;Apte, Suneel S.;Cormier-Daire, Valerie
骨性发育不良是一种常染色体隐性遗传病，其特征为身材矮小、趾短、皮肤厚和心脏瓣膜异常，常导致早期死亡。研究了6个凝胶物理发育不良家族，我们首先将潜在基因定位到染色体9q34.2，并在ADAMTSL2（一种具有血小板反应蛋白重复样2的分解素和金属蛋白酶）中发现了5种不同的无义和错义突变，该突变编码一种功能未知的分泌糖蛋白。HEK293细胞的功能研究表明，ADAMTSL2突变导致突变蛋白的分泌减少，可能是由于ADAMTSL2的错误折叠。酵母双杂交筛选表明，ADAMTSL2与潜在的TGF-β结合蛋白1相互作用。此外，我们观察到培养液中总TGF-β和活性TGF-β的显著增加，以及凝胶物理发育不良个体成纤维细胞中磷酸化SMAD2的核定位。这些数据表明，ADAMTSL2突变可能导致TGF-β信号的失调，并可能是凝胶物理发育不良的潜在机制。
Geleophysic dysplasia is an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin and cardiac valvular anomalies often responsible for an early death. Studying six geleophysic dysplasia families, we first mapped the underlying gene to chromosome 9q34.2 and identified five distinct nonsense and missense mutations in ADAMTSL2 (a disintegrin and metalloproteinase with thrombospondin repeats–like 2), which encodes a secreted glycoprotein of unknown function. Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to reduced secretion of the mutated proteins, possibly owing to the misfolding of ADAMTSL2. A yeast two-hybrid screen showed that ADAMTSL2 interacts with latent TGF-β–binding protein 1. In addition, we observed a significant increase in total and active TGF-β in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia. These data suggest that ADAMTSL2 mutations may lead to a dysregulation of TGF-β signaling and may be the underlying mechanism of geleophysic dysplasia.
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影响因子：
4.8
作者：
Abbaszade, I;Liu, RQ;Burn, TC
通讯作者：
Burn, TC
影响因子：
30.8
作者：
Kinoshita, A;Saito, T;Yoshiura, K
通讯作者：
Yoshiura, K
DOI：
10.1083/jcb.200606058
发表时间：
2006-10-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ge G;Greenspan DS
通讯作者：
Greenspan DS
影响因子：
4.8
作者：
Isogai, Z;Ono, RN;Sakai, LY
通讯作者：
Sakai, LY
影响因子：
6.9
作者：
Koo, Bon-Hun;Le Goff, Carine;Apte, Suneel S.
通讯作者：
Apte, Suneel S.