Unusually mild Tuberous Sclerosis phenotype is associated with TSC2 R905Q mutation
Unusually mild Tuberous Sclerosis phenotype is associated with TSC2 R905Q mutation
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DOI：
10.1002/ana.21037
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发表时间：
2006-11-01
影响因子：
11.2
通讯作者：
Andermann, Eva
中科院分区：
文献类型：
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作者：
Jansen, An C.;Sancak, Ozgur;Andermann, Eva
目的：目的：报道由TSC 2基因905密码子突变引起的多发性硬化综合征（TSC）的临床表现和功能特点。方法：我们对一个法裔加拿大家系（A家族）的TSC表型和基因型进行了详细的研究。随后，收集了另外18个TSC家族的临床和分子数据，这些家族在TSC 2的相同密码子处具有错义突变。结果：在A家系中发现一个2714G > A（R905Q）突变。该家族的TSC表型异常轻微，特征为黑色素减少性斑疹或局灶性癫痫发作，可自发缓解或易于药物控制。只有少数突变携带者符合诊断标准。发现其他具有R905Q突变的家族具有类似的轻度表型。相比之下，2713C > T（R905W）或2713C > G（R905G）突变患者的表型更严重。虽然所有三个氨基酸取代都是致病性的，但R905W和R905G取代对块茎蛋白功能的影响比R905Q更严重。解释：TSC 2中密码子905错义突变相对常见。TSC2 R905Q突变与异常轻微的疾病相关，与功能研究一致。结合以前的报道，很明显，某些TSC 2错义突变与轻度结节性硬化症有关，在许多患者中不符合标准诊断标准。这些发现对大量临床特征有限的TSC患者和这些家庭的遗传咨询具有重要意义。
Objective: To report the clinical manifestations and functional aspects of Tuberous Sclerosis Complex (TSC), resulting from Codon 905 mutations in TSC2 gene.Methods: We performed a detailed study of the TSC phenotype and genotype in a large French-Canadian kindred (Family A). Subsequently, clinical and molecular data on 18 additional TSC families with missense mutations at the same codon of TSC2 were collected. Functional studies were performed on the different missense changes and related to the phenotype.Results: A 2714G > A (R905Q) mutation was identified in Family A. The TSC phenotype in this family was unusually mild and characterized by hypomelanotic macules or focal seizures that remitted spontaneously or were easily controlled with medication. Diagnostic criteria were met in only a minority of mutation carriers. Other families with the R905Q mutation were found to have a similar mild phenotype. In contrast, patients with a 2713C > T (R905W) or a 2713C > G (R905G) mutation had more severe phenotypes. Although all three amino acid substitutions were pathogenic, the R905W and R905G substitutions affected tuberin function more severely than R905QInterpretation: Codon 905 missense mutations in TSC2 are relatively common. The TSC2 R905Q mutation is associated with unusually mild disease, consistent with functional studies. Combined with previous reports, it is apparent that certain TSC2 missense mutations are associated with a mild form of tuberous sclerosis, which in many patients does not meet standard diagnostic criteria. These findings have implications for the large number of patients with limited clinical features of TSC and for genetic counseling in these families.