Beauchamp R L, Banwell A, McNamara P, Jacobsen M, Higgins E, Northrup H, Short P, Sims K, Ozelius L, Ramesh V
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.
Hum Mutat. 1998;12(6):408-16. doi: 10.1002/(SICI)1098-1004(1998)12:6<408::AID-HUMU7>3.0.CO;2-P.
Tuberous sclerosis complex (TSC) is a dominantly inherited multisystem disorder resulting in the development of hamartomatous growths in many organs. Genetic heterogeneity has been demonstrated linking the familial cases to either TSC1 at 9q34.3, or TSC2 at 16p13.3. About two-thirds of the TSC cases are sporadic and appear to represent new mutations. While both genes are thought to account for all familial cases, with each representing approximately 50% of the mutations, the proportion of sporadic cases with mutations in TSC1 and TSC2 is yet to be determined. We have examined the entire coding sequence of the TSC2 gene in 20 familial and 20 sporadic cases and identified a total of twenty-one mutations representing 50% and 55% of familial and sporadic cases respectively. Our rate of mutation detection is significantly higher than other published reports. Twenty out of 21 mutations are novel and include 6 missense, 6 nonsense, 5 frameshifts, 2 splice alterations, a 34 bp deletion resulting in abnormal splicing, and an 18 bp deletion which maintains the reading frame. The mutations are distributed throughout the coding sequence with no specific hot spots. There is no apparent correlation between mutation type and clinical severity of the disease. Our results document that at least 50% of sporadic cases arise from mutations in the TSC2 gene. The location of the mutations described here, particularly the missense events, should be valuable for further functional analysis of this tumor suppressor protein.
结节性硬化症（TSC）是一种显性遗传的多系统疾病，可导致多个器官出现错构瘤性生长。已证实基因异质性将家族性病例与9q34.3的TSC1或16p13.3的TSC2联系起来。约三分之二的TSC病例为散发性，似乎代表新的突变。虽然认为这两个基因可解释所有家族性病例，每个基因约占突变的50%，但TSC1和TSC2中发生突变的散发性病例的比例尚未确定。我们检测了20例家族性病例和20例散发性病例中TSC2基因的整个编码序列，共鉴定出21个突变，分别占家族性病例和散发性病例的50%和55%。我们的突变检测率显著高于其他已发表的报告。21个突变中有20个是新的，包括6个错义突变、6个无义突变、5个移码突变、2个剪接改变、一个导致异常剪接的34 bp缺失和一个保持阅读框的18 bp缺失。突变分布在整个编码序列中，没有特定的热点。突变类型与疾病临床严重程度之间没有明显的相关性。我们的结果证明，至少50%的散发性病例源于TSC2基因的突变。本文所述突变的位置，特别是错义事件，对于该肿瘤抑制蛋白的进一步功能分析应该是有价值的。
