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 Valérie
Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Nat Genet. 2008 Sep;40(9):1119-23. doi: 10.1038/ng.199.
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-beta-binding protein 1. In addition, we observed a significant increase in total and active TGF-beta 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-beta signaling and may be the underlying mechanism of geleophysic dysplasia.
弹力纤维发育异常是一种常染色体隐性疾病，其特征为身材矮小、短指畸形、皮肤增厚以及心脏瓣膜异常，这些异常常导致早期死亡。通过对六个弹力纤维发育异常家族的研究，我们首先将相关基因定位到9号染色体长臂34.2区，并在ADAMTSL2（一种含血小板反应蛋白基序的解聚素样金属蛋白酶2）中鉴定出五个不同类型的无义突变和错义突变，该基因编码一种功能未知的分泌型糖蛋白。在HEK293细胞中进行的功能研究表明，ADAMTSL2突变导致突变蛋白分泌减少，这可能是由于ADAMTSL2错误折叠所致。酵母双杂交筛选显示，ADAMTSL2与潜伏性转化生长因子β结合蛋白1相互作用。此外，我们观察到弹力纤维发育异常个体的成纤维细胞培养基中总转化生长因子β和活性转化生长因子β显著增加，以及磷酸化SMAD2的核定位。这些数据表明，ADAMTSL2突变可能导致转化生长因子β信号传导失调，这可能是弹力纤维发育异常的潜在机制。
