Protein Tyrosine Phosphatase PTPN14 Is a Regulator of Lymphatic Function and Choanal Development in Humans
Protein Tyrosine Phosphatase PTPN14 Is a Regulator of Lymphatic Function and Choanal Development in Humans
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DOI：
10.1016/j.ajhg.2010.08.008
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发表时间：
2010-09-10
影响因子：
9.8
通讯作者：
Diaz, George A.
中科院分区：
文献类型：
--
作者：
Au, Audrey C.;Hernandez, Paolo A.;Diaz, George A.
淋巴管系统是细胞外液再循环、脂肪吸收和免疫功能的关键，也是肿瘤转移的途径。组织特异性淋巴管内皮标记物的鉴定和先天性淋巴水肿综合征的研究加速了对淋巴管生成的分子机制的剖析。我们报告一家系遗传一种独特的常染色体隐性遗传性淋巴水肿-后鼻孔闭锁综合征的结果。这些研究确定了该性状与染色体1q32-q41的联系，并发现了编码非受体酪氨酸磷酸酶的PTPN14功能缺失突变。PTPN14缺乏的原因是通过建立小鼠Ptpn14基因陷阱模型来证实的，该模型表现为淋巴增生和淋巴水肿。生化研究表明，PTPN14与血管内皮生长因子受体3(VEGFR3)之间存在潜在的相互作用，VEGFR3是一种对淋巴管生成至关重要的受体酪氨酸激酶。这些结果表明，PTPN14在哺乳动物淋巴发育的调节中具有独特而保守的作用，而在人类的后鼻孔发育中具有非保守的作用。
The lymphatic vasculature is essential for the recirculation of extracellular fluid, fat absorption, and immune function and as a route of tumor metastasis. The dissection of molecular mechanisms underlying lymphangiogenesis has been accelerated by the identification of tissue-specific lymphatic endothelial markers and the study of congenital lymphedema syndromes. We report the results of genetic analyses of a kindred inheriting a unique autosomal-recessive lymphedema-choanal atresia syndrome. These studies establish linkage of the trait to chromosome 1q32-q41 and identify a loss-of-function mutation in PTPN14, which encodes a nonreceptor tyrosine phosphatase. The causal role of PTPN14 deficiency was confirmed by the generation of a murine Ptpn14 gene trap model that manifested lymphatic hyperplasia with lymphedema. Biochemical studies revealed a potential interaction between PTPN14 and the vascular endothelial growth factor receptor 3 (VEGFR3), a receptor tyrosine kinase essential for lymphangiogenesis. These results suggest a unique and conserved role for PTPN14 in the regulation of lymphatic development in mammals and a nonconserved role in choanal development in humans.