Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal γ subunit
Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal γ subunit
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DOI：
10.1086/506257
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发表时间：
2006-08-01
影响因子：
9.8
通讯作者：
Mundlos, Stefan
中科院分区：
文献类型：
--
作者：
Hoffmann, Katrin;Mueller, Juliane S.;Mundlos, Stefan
埃斯科瓦尔综合征是一种先天性多发性关节弯曲症，以关节挛缩、翼状胬肉和呼吸窘迫为特征。类似的发现发生在新生儿暴露于烟碱能乙酰胆碱受体（AChR）抗体从肌无力的母亲。我们在埃斯科瓦尔综合征家族中进行了连锁研究，并确定了AChR γ亚基基因（CHRNG）内的8个突变。我们的功能研究表明，g-亚基突变防止胎儿AChR在人胚肾细胞膜的正确定位，在产前小鼠的表达模式对应于人类的临床表型。乙酰胆碱受体有五个亚单位。两个α，一个β和一个δ亚基总是存在的。通过在胎儿发育后期将γ亚基转换为γ亚基，胎儿AChR逐渐被成人AChR取代。胎儿和成人AChR是神经肌肉信号转导所必需的。此外，胎儿AChRs似乎是轴突和肌肉初次相遇的向导。由于在器官形成中的重要功能，人类g亚基的突变被认为是致命的，就像在γ基因敲除小鼠中一样。相反，其他亚基中的许多突变被发现是可行的，但引起出生后持续或开始肌无力综合征。我们的结论是埃斯科瓦尔综合征是一种遗传性胎儿肌无力疾病，也影响神经肌肉器官发生。因为g蛋白的表达仅限于早期发育，所以患者在以后的生活中不会出现肌无力症状。这是与其他AChR亚基突变的主要区别，并且与当母体AChR自身抗体穿过胎盘并引起AChR通路暂时失活时在患有关节挛缩症的新生儿中发现的症状惊人地相似。
Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma-subunit gene (CHRNG) of the AChR. Our functional studies show that g-subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the g subunit were thought to be lethal, as they are in gamma-knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because g expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway.