BRCA2 T2722R is a deleterious allele that causes exon skipping
BRCA2 T2722R is a deleterious allele that causes exon skipping
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DOI：
10.1086/342192
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发表时间：
2002-09-01
影响因子：
9.8
通讯作者：
Olopade, OI
中科院分区：
文献类型：
--
作者：
Fackenthal, JD;Cartegni, L;Olopade, OI
有乳腺癌家族史的患者经常被建议接受BRCA1和BRCA2突变的基因筛查，这是已知的最强的乳腺癌预测因子。基因检测的一个主要限制是由于未分类的BRCA1和BRCA2序列变异而导致的不确定结果的数量。许多已知的有害BRCA1和BRCA2突变会影响剪接，这些突变通常位于内含子/外显子边界附近。然而，也存在潜在的内部外显子突变，扰乱功能外显子剪接增强子(ESE)序列，导致外显子跳过。使用先前建立的序列矩阵来对可能的ESE基序进行评分，我们系统地检测了几个BRCA2突变，以寻找潜在的ESE中断突变。这些预测表明，BRCA2 T2722R(8393C-->；G)在一个乳腺癌家庭中与受影响的个体分离，扰乱了三个潜在的ESE位点。逆转录聚合酶链式反应分析证实，该突变导致外显子跳跃，导致BRCA2外显子17和19的框架外融合。这是第一个被证明是预测的有害蛋白截断突变的BRCA2错义突变，为确定BRCA1和BRCA2中许多未分类变异的子集的临床意义提供了一种潜在的有用方法。
Patients with a strong family history of breast cancer are often counseled to receive genetic screening for BRCA1 and BRCA2 mutations, the strongest known predictors of breast cancer. A major limitation of genetic testing is the number of inconclusive results due to unclassified BRCA1 and BRCA2 sequence variants. Many known deleterious BRCA1 and BRCA2 mutations affect splicing, and these typically lie near intron/exon boundaries. However, there are also potential internal exonic mutations that disrupt functional exonic splicing enhancer (ESE) sequences, resulting in exon skipping. Using previously established sequence matrices for the scoring of putative ESE motifs, we have systematically examined several BRCA2 mutations for potential ESE disruption mutations. These predictions revealed that BRCA2 T2722R (8393C-->G), which segregates with affected individuals in a family with breast cancer, disrupts three potential ESE sites. Reverse-transcriptase polymerase chain reaction analysis confirms that this mutation causes exon skipping, leading to an out-of-frame fusion of BRCA2 exons 17 and 19. This represents the first BRCA2 missense mutation shown to be a predicted deleterious protein-truncating mutation and suggests a potentially useful method for determining the clinical significance of a subset of the many unclassified variants in BRCA1 and BRCA2.