An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders.
An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders.
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DOI：
10.1016/j.cell.2013.01.038
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发表时间：
2013-02-28
期刊：
影响因子：
64.5
通讯作者：
Zoghbi HY
中科院分区：
文献类型：
--
作者：
Baker SA;Chen L;Wilkins AD;Yu P;Lichtarge O;Zoghbi HY
X连锁MECP2的突变会导致Rett综合征，这是一种毁灭性的神经疾病，其特征是一段时间的明显正常发育，然后是认知和精神运动技能的丧失。来自罕见男性患者的数据表明，突变的位置可能会影响症状的出现和严重程度，氨基酸270和273一方面标志着新生儿脑病和死亡，另一方面标志着缺陷生存。因此，我们建立了两个表达MeCP2-R270X或MeCP2-G273X的小鼠模型。随着时间的推移，这些小鼠以惊人的不同速度发展表型，并在神经系统内表现出不同的ATRX核定位，与表型进展相一致。我们发现MeCP2在250个氨基酸中含有3个AT-钩状结构域，类似于HMGA DNA弯曲蛋白；在MeCP2-R270X中有一个保守的AT-挂钩被破坏，进一步支持了MeCP2的S的关键功能之一是改变染色质结构的观点。
Mutations in the X-linked MECP2 cause Rett syndrome, a devastating neurological disorder typified by a period of apparently normal development followed by loss of cognitive and psychomotor skills. Data from rare male patients suggest symptom onset and severity can be influenced by the location of the mutation, with amino acids 270 and 273 marking the difference between neonatal encephalopathy and death, on the one hand, and survival with deficits on the other. We therefore generated two mouse models expressing either MeCP2-R270X or MeCP2-G273X. The mice developed phenotypes at strikingly different rates and showed differential ATRX nuclear localization within the nervous system, over time, coinciding with phenotypic progression. We discovered that MeCP2 contains three AT-hook-like domains over a stretch of 250 amino acids, like HMGA DNA-bending proteins; one conserved AT-hook is disrupted in MeCP2-R270X, lending further support to the notion that one of MeCP2’s key functions is to alter chromatin structure.
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