Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs
Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs
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DOI：
10.1086/316951
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发表时间：
2001-01-01
影响因子：
9.8
通讯作者：
Kwiatkowski, DJ
中科院分区：
文献类型：
--
作者：
Dabora, SL;Jozwiak, S;Kwiatkowski, DJ
结节性硬化症（TSC）是一种相对常见的错构瘤综合征，由TSC1和TSC2两个基因中的任何一个突变引起。本文报告了224例TSC患者的综合突变分析，并将突变结果与临床特征相关联，采用变性高效液相色谱法、远程聚合酶链反应（PCR）和定量PCR进行突变检测。224例中有186例（83%）发生突变，其中TSC2小突变138例，TSC2大突变20例，TSC1小突变28例。采用标准化临床评估工具，涵盖16种TSC表现。与TSC2突变患者相比，散发性TSC1突变患者的平均病情较轻，尽管年龄相似。他们有较低的癫痫发作频率和中重度精神发育迟滞，较少的室管膜下结节和皮质结节，较轻的肾脏受损伤，无视网膜错构瘤和较轻的面部血管纤维瘤。平均而言，未发现突变的患者的疾病也比TSC2突变的患者轻，与TSC1突变的患者有所不同。尽管TSC1与TSC2突变患者的许多临床特征在谱上有重叠，但一些特征（2-4级肾囊肿或血管平滑肌脂肪瘤、前额斑块、视网膜错构瘤和肝脏血管平滑肌脂肪瘤）在TSC1患者中非常罕见或根本未见。因此，生殖系和体细胞突变在TSC1中似乎比在TSC2中更少见。在没有明确突变的患者中，疾病严重程度降低表明，这些患者中有许多是镶嵌TSC2突变和/或由于尚未确定的位点突变而患有TSC，其临床表型相对较轻。
Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused by mutations in either of two genes, TSC1 and TSC2. Here we report comprehensive mutation analysis in 224 index patients with TSC and correlate mutation findings with clinical features, Denaturing high-performance liquid chromatography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. A standardized clinical assessment instrument covering 16 TSC manifestations was used. Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and was somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relatively mild clinical phenotype.