Evidence for SH2 Domain-Containing 5′-Inositol Phosphatase-2 (SHIP2) Contributing to a Lymphatic Dysfunction

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.

淋巴管系统（lymphatic vasculature）在多种患病率持续攀升的疾病中发挥关键作用，包括自身免疫性疾病、肥胖症、血管疾病以及癌症转移。与血管系统不同，目前仍缺乏用于解析淋巴管功能障碍/疾病分子机制的研究工具。近年来，有研究者报道PI3K信号通路（PI3K pathway）失调可引发伴淋巴管系统异常的综合征性人类疾病，但鲜有确凿证据证实该分子通路与人类淋巴管功能障碍存在直接关联。本研究针对一例非综合征性淋巴管疾病家系，采用近红外荧光淋巴管成像（near-infrared fluorescence lymphatic imaging, NIRFLI）完成表型分析，并通过下一代测序（next generation sequencing, NGS）开展无偏倚遗传筛查，最终发现编码SHIP2蛋白的INPPL1基因存在一处罕见新发突变；SHIP2作为PI3K信号通路的负调控因子，该突变与该家系的淋巴管功能障碍显著相关。体外实验探究显示，SHIP2可直接导致正常淋巴管内皮细胞（lymphatic endothelial cell, LEC）行为受损，且SHIP2可与淋巴水肿相关受体结合，提示其直接参与淋巴管系统的生理病理过程。