Department of Craniofacial Development and Stem Cell Biology, King's College London, Guy's Tower, London, United Kingdom.
Dev Dyn. 2012 Aug;241(8):1310-24. doi: 10.1002/dvdy.23812. Epub 2012 Jun 26.
22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, characterized by cardiovascular defects such as interrupted aortic arch, outflow tract defects, thymus and parathyroid hypo- or aplasia, and cleft palate. Heterozygosity of Tbx1, the mouse homolog of the candidate TBX1 gene, results in mild defects dependent on genetic background, whereas complete inactivation results in severe malformations in multiple tissues.
The loss of function of two Sprouty genes, which encode feedback antagonists of receptor tyrosine kinase (RTK) signaling, phenocopy many defects associated with 22q11DS in the mouse. The stepwise reduction of Sprouty gene dosage resulted in different phenotypes emerging at specific steps, suggesting that the threshold up to which a given developmental process can tolerate increased RTK signaling is different. Tbx1 heterozygosity significantly exacerbated the severity of all these defects, which correlated with a substantial increase in RTK signaling.
Our findings suggest that TBX1 functions as an essential component of a mechanism that protects the embryo against perturbations in RTK signaling that may lead to developmental defects characteristic of 22q11DS. We propose that genetic factors that enhance RTK signaling ought to be considered as potential genetic modifiers of this syndrome.
22q11.2 缺失综合征（22q11DS）是人类最常见的微缺失综合征，其特征为心血管缺陷，如主动脉弓中断、流出道缺陷、胸腺和甲状旁腺发育不全或发育不良以及腭裂。候选 TBX1 基因的小鼠同源物 Tbx1 的杂合性导致依赖遗传背景的轻度缺陷，而完全失活则导致多种组织的严重畸形。
两个 Sprouty 基因（编码受体酪氨酸激酶（RTK）信号反馈拮抗剂）的功能丧失，在小鼠中模拟了与 22q11DS 相关的许多缺陷。Sprouty 基因剂量的逐步降低导致在特定步骤出现不同的表型，表明给定发育过程能够耐受增加的 RTK 信号的阈值是不同的。Tbx1 杂合性显著加重了所有这些缺陷的严重程度，这与 RTK 信号的显著增加有关。
我们的研究结果表明，TBX1 作为一种机制的重要组成部分发挥作用，该机制可保护胚胎免受可能导致 22q11DS 特征性发育缺陷的 RTK 信号扰动。我们提出，增强 RTK 信号的遗传因素应被视为该综合征的潜在遗传修饰因子。
