ERBIN and phosphoglucomutase 3 deficiency.
ERBIN and phosphoglucomutase 3 deficiency.
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DOI：
10.1016/j.coi.2023.102353
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发表时间：
2023-06
影响因子：
7
通讯作者：
J. Milner
中科院分区：
文献类型：
--
作者：
J. Milner
亮点Erbin杂合突变通过STAT3扰乱对TGFb信号的调节。Erbin功能缺失将特应性和结缔组织异常联系在一起，这些异常见于TGFb和STAT3信号异常。PGM3缺乏过敏、宿主防御缺陷、结缔组织和发育异常。这两种疾病都可能与IL-6/STAT3信号通路重叠。ERBIN和磷酸葡萄糖变位酶3(PGM3)突变都导致罕见的以过敏性疾病和结缔组织异常为特征的原发性特应性疾病，尽管每种疾病都有其独特的多系统表现模式。通路研究表明Erbin突变如何增强TGFb信号，并阻止STAT3负调控TGFb信号。这可能解释了STAT3和TGFb信号紊乱之间临床重叠的许多因素。过度的TGFb信号导致IL-4受体表达增加，也为精确阻断IL-4受体治疗特应性疾病提供了理论基础。PGM3缺乏导致特应性表型的机制尚不清楚，疾病外显性和表达能力的广泛变异性也不是很清楚，尽管初步研究表明与IL-6受体信号缺陷有重叠。
HighlightsHeterozygous mutations in ERBIN disrupt regulation of TGFb signaling via STAT3.Loss of ERBIN function links the atopic and connective tissue abnormalities seen in disorders of TGFb and STAT3 signaling.PGM3 deficiency allergy, host defense defects, connective tissue, and developmental abnormalities.Both disorders potentially overlap with the IL-6/STAT3 signaling pathway.ERBIN and phosphoglucomutase 3 (PGM3) mutations both lead to rare primary atopic disorders characterized by allergic disease and connective tissue abnormalities, though each disorder has its own rather unique pattern of multisystem presentations. Pathway studies show how ERBIN mutations allow for enhanced TGFb signaling, and prevent STAT3 from negative-regulating TGFb signaling. This likely explains many elements of clinical overlap between disorders of STAT3 and TGFb signaling. The excessive TGFb signaling leading to increased IL-4 receptor expression also provides the rationale for precision-based therapy blocking the IL-4 receptor to treat the atopic disease. The mechanism by which PGM3 deficiency leads to atopic phenotypes is not well understood, nor is the broad variability in disease penetrance and expressivity, though preliminary studies suggest an overlap with IL-6 receptor signaling defects.