Three independent mutations in the TSC2 gene in a family with tuberous sclerosis.
Three independent mutations in the TSC2 gene in a family with tuberous sclerosis.
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DOI：
10.1038/ejhg.2009.28
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发表时间：
2009-09
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影响因子：
--
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结节性硬化症（TSC）是一种罕见的常染色体显性遗传病，以错构瘤和多器官错构瘤为特征。TSC是由TSC1和TSC2基因内的广泛突变引起的。在这里，我们报告了一个独特的家族，在TSC2中有三个独立的病理突变。第12外显子的c.1322G > A突变产生了一个停止密码子，而第23外显子的第二个突变（c.2713C >t）是一个错义改变。第三个突变是TSC2的内含子20缺失4个碱基对。我们发现这种突变是导致异常剪接的原因。这三种突变最有可能是从头开始的，因为受影响患者的父母没有表现出TSC的任何特征。此外，我们还在该家族的一个分支中发现了性腺镶嵌现象。据我们所知，TSC2的几个独立突变从未在单个家族中观察到。发现一个家庭有三种不同的病理性TSC2突变的可能性非常低。我们讨论可能提出的两个主要假设来解释这种复发：(i) TSC2突变率被低估了。在这种情况下，发现一个家庭有三个独立的TSC2突变的可能性可能不会很低；（ii）在与TSC2基因无关的家族中分离的DNA修复基因（如错配修复基因）的可遗传缺陷可能易导致多个TSC2基因突变的发生，这在胚胎发生期间被用作特定靶点。
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by hamartomas and hamartias in multiple organs. TSC is caused by a wide spectrum of mutations within the TSC1 and TSC2 genes. Here, we report a unique family with three independent pathological mutations in TSC2. A c.1322G > A mutation in exon 12 created a stop codon, whereas a second mutation in exon 23 (c.2713C > T) was a missense change. The third mutation was a 4 base pair deletion in intron 20 of TSC2. We showed that this mutation was responsible for abnormal splicing. The three mutations were most likely de novo, as parents of affected patients did not present any features of TSC. In addition, we showed gonadal mosaicism in a branch of the family. To our knowledge, several independent mutations in TSC2 have never been observed in a single family. The probability of finding a family with three different pathological TSC2 mutations is extremely low. We discuss two main hypotheses that may be raised to explain this recurrence: (i) the TSC2 mutation rate is underestimated. In such a case, the likelihood of finding a family with three independent mutations in TSC2 may not be dramatically low; (ii) a heritable defect in a DNA repair gene (eg, mismatch repair gene) segregating in the family that is unlinked to the TSC2 gene might predispose to the occurrence of multiple TSC2 gene mutations, used as a specific target during embryogenesis.
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影响因子：
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