IRIBHM, Campus Erasme, ULB Bâtiment C, Bruxelles, Belgium.
Department of Medical Genetics, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes-Sorbonne Paris Cité University, AP-HP, Institut Imagine, Paris, France.
Hum Mutat. 2017 Dec;38(12):1731-1739. doi: 10.1002/humu.23321. Epub 2017 Sep 21.
The SH2 domain containing inositol phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, a lipid involved in the control of cell migration and adhesion. The INPPL1 gene that encodes SHIP2 has been found to be mutated in several cases of opsismodysplasia (OPS), a rare autosomal recessive chondrodysplasia characterized by growth plate defects and delayed bone maturation. Reported mutations often result in premature stop codons or missense mutations in SHIP2 catalytic domain. SHIP2 biochemical properties are known from studies in cancer cells; its role in endochondral ossification is unknown. Here, we report two novel mutations in the INPPL1 gene and show that cell migration is very much decreased in fibroblasts derived from three OPS patients as compared with control individuals. In contrast, cell adhesion on fibronectin is increased in OPS fibroblasts. An inhibitory effect on migration was also observed when normal fibroblasts were incubated in the presence of a SHIP2 competitive inhibitor. We conclude that both migration and adhesion are very much disrupted in OPS-derived fibroblasts. It is suggested that signaling events linked to migration and particularly to adhesion, which are lost in OPS patients, would prevent normal endochondral ossification.
含 SH2 结构域的肌醇磷酸酶 2（SHIP2）可将 PI(3,4,5)P3 去磷酸化为 PI(3,4)P2，后者参与控制细胞迁移和黏附。编码 SHIP2 的 INPPL1 基因已在几种 opsismodysplasia（OPS）病例中发现突变，OPS 是一种罕见的常染色体隐性软骨发育不良，其特征是生长板缺陷和骨成熟延迟。报道的突变通常导致 SHIP2 催化结构域中的提前终止密码子或错义突变。SHIP2 的生化特性已在癌细胞研究中得到证实；但其在软骨内骨化中的作用尚不清楚。在此，我们报道了 INPPL1 基因中的两个新突变，并表明与对照个体相比，来自三名 OPS 患者的成纤维细胞的迁移能力大大降低。相比之下，OPS 成纤维细胞对纤维连接蛋白的黏附性增加。当正常成纤维细胞在 SHIP2 竞争性抑制剂存在的情况下孵育时，也观察到对迁移的抑制作用。我们得出结论，OPS 衍生的成纤维细胞中迁移和黏附都受到严重破坏。提示与迁移特别是黏附相关的信号事件在 OPS 患者中丢失，会阻止正常的软骨内骨化。
