Jones A C, Shyamsundar M M, Thomas M W, Maynard J, Idziaszczyk S, Tomkins S, Sampson J R, Cheadle J P
Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, United Kingdom.
Am J Hum Genet. 1999 May;64(5):1305-15. doi: 10.1086/302381.
Tuberous sclerosis (TSC [MIM 191090 and MIM 191100]) is an autosomal dominant disorder characterized by hamartomas in many organs. Two thirds of cases are sporadic and are thought to represent new mutations. TSC is caused by mutations affecting either of the presumed tumor-suppressor genes, TSC1 and TSC2. Both appear to function as tumor suppressors, because somatic loss or intragenic mutation of the corresponding wild-type allele is seen in the associated hamartomas. Here we report the first comprehensive mutation analysis of TSC1 and TSC2 in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons and using pulsed-field gel electrophoresis and conventional Southern blot analysis and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185). Twenty-two patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (eight cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (eight cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein. Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P=.0145). These data provide the first representative picture of the distribution and spectrum of mutations across the TSC1 and TSC2 loci in clinically ascertained TSC and support a difference in severity of TSC1- and TSC2-associated disease.
结节性硬化症（TSC [MIM 191090和MIM 191100]）是一种常染色体显性疾病，其特征是多个器官出现错构瘤。三分之二的病例为散发性，被认为代表新的突变。TSC是由影响假定的肿瘤抑制基因TSC1和TSC2之一的突变引起的。两者似乎都起到肿瘤抑制作用，因为在相关错构瘤中可观察到相应野生型等位基因的体细胞缺失或基因内突变。在此，我们报告了对150名无亲缘关系的TSC患者及其家族进行的TSC1和TSC2的首次全面突变分析，采用对所有编码外显子进行异源双链和单链构象多态性分析，并使用脉冲场凝胶电泳、传统Southern印迹分析和长PCR来筛查大片段重排。在150例病例中的120例（80%）中鉴定出突变，其中22例影响TSC1，98例影响TSC2。TSC1突变在散发性病例中的比例明显过低（P = 0.000185）。22名患者有TSC2错义突变，主要发现于GAP相关结构域（8例）以及外显子16和17编码的一个小区域，核苷酸1849至1859之间（8例），这与这些位点存在执行关键功能的残基一致。相比之下，所有TSC1突变预计均为截短突变，这与编码蛋白的结构或衔接子作用一致。TSC2散发性病例中的智力残疾明显比TSC1散发性病例更常见（P = 0.0145）。这些数据首次提供了临床确诊的TSC中TSC1和TSC2基因座突变分布和谱的代表性情况，并支持TSC1和TSC2相关疾病严重程度的差异。
