Yeast Genetics and Genomics, Laboratory of Functional Genetics and Genomics, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy.
Molecular Genetics Unit, Department of Oncology, University Hospital of Pisa, 56126 Pisa, Italy.
Int J Mol Sci. 2024 Jul 9;25(14):7511. doi: 10.3390/ijms25147511.
, a crucial tumor suppressor gene, has several splicing isoforms, including Δ9-11, Δ11, and Δ11q, which lack exon 11, coding for significant portions of the protein. These isoforms are naturally present in both normal and cancerous cells, exhibiting altered activity compared to the full-length BRCA1. Despite this, the impact on cancer risk of the germline intronic variants promoting the exclusive expression of these Δ11 isoforms remains uncertain. Consequently, they are classified as variants of uncertain significance (VUS), posing challenges for traditional genetic classification methods due to their rarity and complexity. Our research utilizes a yeast-based functional assay, previously validated for assessing missense BRCA1 variants, to compare the activity of the Δ11 splicing isoforms with known pathogenic missense variants. This approach allows us to elucidate the functional implications of these isoforms and determine whether their exclusive expression could contribute to increased cancer risk. By doing so, we aim to provide insights into the pathogenic potential of intronic VUS-generating BRCA1 splicing isoforms and improve the classification of BRCA1 variants.
BRCA1 是一个重要的肿瘤抑制基因，有几种剪接异构体，包括Δ9-11、Δ11 和 Δ11q，它们缺失外显子 11，编码蛋白的重要部分。这些异构体在正常和癌细胞中都自然存在，与全长 BRCA1 相比，其活性发生了改变。尽管如此，促进这些 Δ11 异构体特异性表达的种系内含子变异体对癌症风险的影响仍不确定。因此，它们被归类为意义不明的变异体（VUS），由于其稀有性和复杂性，给传统的遗传分类方法带来了挑战。我们的研究利用了一种基于酵母的功能测定方法，该方法先前已被验证可用于评估错义 BRCA1 变异体，以比较 Δ11 剪接异构体与已知致病性错义变异体的活性。这种方法使我们能够阐明这些异构体的功能意义，并确定它们的特异性表达是否会导致癌症风险增加。通过这样做，我们旨在深入了解产生 BRCA1 剪接异构体的内含子 VUS 的致病潜力，并改善 BRCA1 变异体的分类。
