Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations?-猫眼课题宝

DOI：

10.1136/jmg.40.5.e52

发表时间：

2003-05-01

期刊：

JOURNAL OF MEDICAL GENETICS

影响因子：

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Leonard, H;Colvin, L;Yamashita, Y

澳大利亚。1它的特征是在6至18个月之间明显正常发育，然后是一段退化期，失去有目的的手使用，头部生长减速，开始重复的、刻板印象的手运动。2受影响的人还表现为步态共济失调和失用、自闭症特征、癫痫发作、呼吸功能障碍、自主神经功能障碍和躯体生长减慢。2 3近年来，这种疾病的表型范围比以前认为的要广泛得多，这一点变得很明显。一些患者可能具有较轻的表型并保留行走或说话的能力，而另一些患者则具有较早的发病和较严重的特征。具有部分但不是全部必要标准的人被归类为非典型或六种变异形式之一。5 Rett综合征现已被证明与甲基CpG结合蛋白2(MeCP2)的突变有关。6对于许多遗传性疾病，基因鉴定后的下一阶段研究涉及描述基因型和表型之间的关系，以及同一基因中不同突变所产生的表型多样性。一些研究发现，MECP2错义突变的人可能比截短突变的人有更温和的表型。7、8、Weving等人发现，在错义突变的人中，手部刻板印象开始的年龄较晚，言语和身高(但不是头部生长)略正常，而Nielsen等人发现这些突变类型之间的严重程度没有差异。在Amir等人的研究中，发现11例呼吸异常在截断突变中更常见，脊柱侧弯在错义突变中更常见。Hoffbuhr等人得出结论，甲基结合域(MBD)错义突变和整个转录抑制域(TRD)突变的患者比TRD和C末端片段错义和无义突变的患者受到的影响更严重。同样，在另一项研究中，与早期截断突变相比，较温和的表型与晚期突变相关。13在最近的一篇文章中，Huppke等人将核定位信号(NLS)中的这些突变视为与其他截断突变不同的类别。总体而言，他们发现，突变导致NLS部分或完全截断的病例比TRD下游突变的病例更严重。尽管MECP2内不同类别突变的一些表型关联正在出现，但这些报告受到相对较小的样本量的阻碍。在最近的一篇综述中，实际上有人提出，临床严重性和突变类型之间的简单关系甚至可能不存在。15 MECP2在X染色体上的位置使得X失活模式的改变很可能也会导致表型变异，就像来自同一家庭的杂合子雌性所看到的那样。16偏斜X失活模式与所见表型之间的相关性是否接近仍不确定。在两个最全面报道的研究中，Hoffbuhr等人12在6/39(15%)的病例中发现了偏斜(定义为一个X等位基因的85%活跃)，而Weving等人用更自由的定义(&gt；75%的一个X等位基因活跃)发现了31/72(43%)。与Rett综合征相关的特定突变的功能分析也在进行中。与MBD中的其他一些错义突变类似，R133C突变已被证明取消了甲基化特异性与DNA模板的结合。然而，在后来的一项研究中，工藤等人发现R133C突变体在功能上几乎是…

Australia. 1 It is characterised by apparently normal development between 6 and 18 months, followed by a period of regression with loss of purposeful hand use, deceleration of head growth, and onset of repetitive, stereotypic hand movements. 2 Affected people also manifest gait ataxia and apraxia, autistic features, epileptic seizures, respiratory dysfunction, autonomic dysfunction, and decreased somatic growth. 2 3 In recent years it has become apparent that the phenotypic range of this disorder is much wider than previously thought. Some patients may have a milder phenotype and retain the ability to walk or speak and others have an earlier onset and more severe features. People who have some but not all of the necessary criteria have been categorised as atypical4 or as one of six variant forms. 5 Rett syndrome has now been shown to be associated with mutations in the methyl-CpG-binding protein 2 (MeCP2). 6 For many genetic disorders, the next stage in research after the identification of the gene involves describing the relation between genotype and phenotype, and the phenotypic diversity produced by different mutations in the same gene. Some research has found that people with missense MECP2 mutations may have a milder phenotype than those with truncating mutations. 7 8 Weaving et al9 found that age at onset of hand stereotypies was later and speech and height (but not head growth) were slightly more normal in those with missense mutations whereas Nielsen et al10 found no difference in severity between these mutation types. In the study of Amir et al11 breathing abnormalities were found to be more common with truncating mutations and scoliosis more common with missense mutations. Hoffbuhr et al12 concluded that patients with missense mutations in the methyl binding domain (MBD) and mutations truncating the entire transcription repression domain (TRD) were more severely affected than those with missense and nonsense mutations in the TRD and C terminal segment. Similarly, in another study, a milder phenotype was associated with late compared with early truncating mutations. 13 In a recent publication, Huppke et al14 considered those mutations in the nuclear localisation signal (NLS) as a separate category from the other truncating mutations. Overall, they found that cases with mutations leading to a partial or complete truncation of the NLS were more severe than those with mutations downstream of the TRD. Although some phenotypic associations with different classes of mutations within MECP2 are emerging, the reports are hampered by relatively small sample size. In one recent review, it was actually suggested that a simple relation between clinical severity and type of mutation may not even exist. 15 The location of MECP2 on the X chromosome makes it very likely that altered patterns of X inactivation also contribute to the phenotypic variation as seen in heterozygous females from the same family. 16 The closeness of the correlation between skewed X inactivation patterns and the phenotype seen remains uncertain. In the two most comprehensive reported studies, Hoffbuhr et al12 found skewing (defined as> 85% of one X allele active) in 6/39 (15%) cases whereas Weaving et al9 with a more liberal definition (> 75% of one X allele active) found it in 31/72 (43%).Functional analysis of specific mutations associated with Rett syndrome is now also being undertaken. Similar to some other missense mutations in the MBD, the R133C mutation has been shown to abrogate methylation specific binding to the DNA template. 17 However, in a later study Kudo et al18 found the R133C mutant to be functionally almost …

Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations?

文献摘要

被引文献

相似文献