Evidence for SH2 domain-containing 5'-inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction.
Evidence for SH2 domain-containing 5'-inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction.
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DOI：
10.1371/journal.pone.0112548
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sevick-Muraca EM
中科院分区：
文献类型：
--
作者：
Agollah GD;Gonzalez-Garay ML;Rasmussen JC;Tan IC;Aldrich MB;Darne C;Fife CE;Guilliod R;Maus EA;King PD;Sevick-Muraca EM
淋巴管系统在许多发病率增加的疾病状况中起关键作用，例如自身免疫性疾病、肥胖症、血管疾病和癌症转移。然而，与血管系统不同，一直缺乏可用于询问淋巴功能障碍/疾病的分子基础的工具。最近，研究人员报道PI 3 K通路的失调与涉及异常淋巴管的综合征性人类疾病有关，但很少有令人信服的结果表明该分子通路与人类淋巴功能障碍直接相关。使用近红外荧光淋巴成像（NIRFLI）表型和下一代测序（NGS）在一个非综合征性淋巴疾病家族中进行无偏见的遗传发现，我们发现了一种罕见的INPPL 1新突变，该突变编码蛋白SHIP 2，这是PI 3 K通路的负调节因子，与家族中的淋巴功能障碍有关。体外研究表明，SHIP 2与正常淋巴管内皮细胞（LEC）行为的损害直接相关，SHIP 2与水肿相关的受体相关，暗示其直接参与淋巴管系统。
The lymphatic vasculature plays a critical role in a number of disease conditions of increasing prevalence, such as autoimmune disorders, obesity, blood vascular diseases, and cancer metastases. Yet, unlike the blood vasculature, the tools available to interrogate the molecular basis of lymphatic dysfunction/disease have been lacking. More recently, investigators have reported that dysregulation of the PI3K pathway is involved in syndromic human diseases that involve abnormal lymphatic vasculatures, but there have been few compelling results that show the direct association of this molecular pathway with lymphatic dysfunction in humans. Using near-infrared fluorescence lymphatic imaging (NIRFLI) to phenotype and next generation sequencing (NGS) for unbiased genetic discovery in a family with non-syndromic lymphatic disease, we discovered a rare, novel mutation in INPPL1 that encodes the protein SHIP2, which is a negative regulator of the PI3K pathway, to be associated with lymphatic dysfunction in the family. In vitro interrogation shows that SHIP2 is directly associated with impairment of normal lymphatic endothelial cell (LEC) behavior and that SHIP2 associates with receptors that are associated in lymphedema, implicating its direct involvement in the lymphatic vasculature.
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