Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes
Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes
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DOI：
10.1002/1531-8249(200005)47:5
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发表时间：
2000-05-01
影响因子：
11.2
通讯作者：
Zoghbi, HY
中科院分区：
文献类型：
--
作者：
Amir, RE;Van den Veyver, IB;Zoghbi, HY
通过直接测序法对71例散发性和7例家族性Rett综合征（RTT）患者进行了MECP 2突变筛查，并确定了39例RTT患者的X染色体失活（XCI）模式。我们在71例散发性患者中的54例（76%）和7例家族性病例中的2例（29%）中确定了23种不同的致病MECP2突变。我比较了携带错义突变和携带截短突变的患者的电生理结果，脑脊液神经化学和13个临床特征。34例经典RTT患者中有31例（31%）有随机XCI。非随机XCI与较温和的表型相关，包括由罕见的早期截短突变引起的减轻的经典RTT。截短突变患者清醒时呼吸功能障碍的发生率较高，脑脊液高香草酸水平较低。脊柱侧弯在有错义突变的患者中更常见。这些数据表明，不同的MECP2突变具有相似的表型结果，并且随机XCI在产生经典RTT的全表型谱中起重要作用。早期截短突变与非随机XCI的关联，沿着缺乏甲基CpG结合蛋白2（MeCP 2）功能的嵌合小鼠在胚胎发生期间死亡的事实，支持RTT是由MeCP 2功能的部分丧失引起的观点。
Me screened 71 sporadic and 7 familiar Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome inactivation (XCI) in 39 RTT patients. We identified 23 different disease-causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. Me compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty-one of 34 patients (31%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.