Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers
Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers
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DOI：
10.1038/sj.ejhg.5201682
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发表时间：
2006-11-01
影响因子：
5.2
通讯作者：
Orstavik, Karen Helene
中科院分区：
文献类型：
--
作者：
Knudsen, Gun Peggy S.;Neilson, Tracey C. S.;Orstavik, Karen Helene
Rett综合征是一种主要是散发性的、X连锁的神经系统疾病，具有特征性的表型，但表现出很大的表型变异。这种变异部分归因于X染色体失活(XCI)的影响。关于Rett综合征中X失活偏斜的发生率，有相互矛盾的报道。在罕见的Rett综合征家族病例中，在表型正常的携带者母亲中发现了有利的偏斜X失活。我们研究了散发性RETT患者(n=96)及其母亲(n=84)的血液和口腔细胞DNA中的X失活模式。患者组平均偏斜度(70.7%)高于对照组(64.9%)。出乎意料的是，这些患者的母亲的平均血液偏斜度(70.8%)也高于对照组。根据这些发现，血液中偏态(XCI和GT；=80%)X失活的频率在患者(25%)和母亲(30%)中也高于对照组(11%)。为了检验X偏向失活的RETT患者是否是偏向母亲的女儿，对49对母女进行了分析。在14名X偏失活的患者中，只有3名母亲的X偏失活。在患者中，受轻度影响的患者比受影响更严重的患者表现出更多的偏斜，并且在偏斜的病例中，父系遗传的X染色体有优先失活的趋势。这些发现，特别是在Rett综合征患者中更大程度的X失活偏斜，对于分析Rett综合征的基因-表型相关性具有潜在的意义。
Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of skewed X inactivation in Rett syndrome. In rare familial cases of Rett syndrome, favourably skewed X inactivation has been found in phenotypically normal carrier mothers. We have investigated the X inactivation pattern in DNA from blood and buccal cells of sporadic Rett patients (n = 96) and their mothers (n = 84). The mean degree of skewing in blood was higher in patients (70.7%) than controls (64.9%). Unexpectedly, the mothers of these patients also had a higher mean degree of skewing in blood (70.8%) than controls. In accordance with these findings, the frequency of skewed (XCI >= 80%) X inactivation in blood was also higher in both patients (25%) and mothers (30%) than in controls (11%). To test whether the Rett patients with skewed X inactivation were daughters of skewed mothers, 49 mother - daughter pairs were analysed. Of 14 patients with skewed X inactivation, only three had a mother with skewed X inactivation. Among patients, mildly affected cases were shown to be more skewed than more severely affected cases, and there was a trend towards preferential inactivation of the paternally inherited X chromosome in skewed cases. These findings, particularly the greater degree of X inactivation skewing in Rett syndrome patients, are of potential significance in the analysis of genotype - phenotype correlations in Rett syndrome.