Niida Y, Lawrence-Smith N, Banwell A, Hammer E, Lewis J, Beauchamp R L, Sims K, Ramesh V, Ozelius L
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Hum Mutat. 1999;14(5):412-22. doi: 10.1002/(SICI)1098-1004(199911)14:5<412::AID-HUMU7>3.0.CO;2-K.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of multiple hamartomas involving many organs. About two-thirds of the cases are sporadic and appear to represent new mutations. With the cloning of two causative genes, TSC1 and TSC2 it is now possible to analyze both genes in TSC patients and identify germline mutations. Here we report the mutational analysis of the entire coding region of both TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by single-stranded conformational polymorphism (SSCP) analysis followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial cases) and 58 TSC2 mutations (42 sporadic and 16 familial cases). Overall, significantly more TSC2 mutations were found in our population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (P = 0.0035, Fisher's exact test). All TSC1 mutations were predicted to be protein truncating. However, in TSC2 13 missense mutations were found, five clustering in the GAP-related domain and three others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, we could not find any observable differences between TSC1 and TSC2 patients. Our data help define the distribution and spectrum of mutations associated with the TSC loci and will be useful for both understanding the function of these genes as well as genetic counseling in patients with the disease.
结节性硬化症（TSC）是一种常染色体显性疾病，其特征是多个器官出现错构瘤。约三分之二的病例为散发性，似乎代表新的突变。随着致病基因TSC1和TSC2的克隆，现在有可能对TSC患者的这两个基因进行分析并鉴定种系突变。在此，我们报告通过单链构象多态性（SSCP）分析随后直接测序，对126例无亲缘关系的TSC患者（包括40例家族性和86例散发性病例）的TSC1和TSC2基因整个编码区进行的突变分析。共在74例（59%）病例中鉴定到突变，包括16例TSC1突变（5例散发性和11例家族性病例）和58例TSC2突变（42例散发性和16例家族性病例）。总体而言，在我们的人群中发现的TSC2突变明显更多，在家族性病例中TSC1和TSC2之间的突变分布相对均等，但在散发性病例中TSC1突变明显较少（P = 0.0035，Fisher精确检验）。所有TSC1突变预计会导致蛋白质截短。然而，在TSC2中发现了13个错义突变，5个集中在GAP相关结构域，另外3个在外显子16中。在比较包括智力残疾发生率在内的临床表现时，我们未发现TSC1和TSC2患者之间有任何可观察到的差异。我们的数据有助于确定与TSC基因座相关的突变分布和谱，对于理解这些基因的功能以及为该疾病患者提供遗传咨询均将有用。
