背景:BMPR1A介导的信号转导在肠道生长中起重要作用。BMPR1A的变异导致罕见的常染色体显性遗传幼年性息肉病综合征(JPS),很有可能发展为结直肠癌(CRC)。胡说八道和移码变化,生成过早终止密码子(PTC),是BMPR1A基因中最具致病性的变异体。
目的:本研究旨在探讨一个中国三代CRC家系的分子遗传学病因。
方法:使用下一代测序平台,通过多基因小组测试,在一个中国CRC家族中检测了18个已知CRC易感基因的致病变异。通过Sanger测序在家族成员中验证了候选基因变体。在RKO结肠癌细胞系中进一步研究了该基因变体的潜在生物学功能。
结果:一种新颖的无义变体(c.1114A>T,在CRC家族中鉴定出BMPR1A的p.Lys372*)。该变体在激酶结构域产生PTC并引起无义介导的mRNA衰变。通读诱导试剂G418和PTC124部分恢复BMPR1A表达及其后续信号传导途径。
结论:新型BMPR1A变体的鉴定丰富了BMPR1A的基因型-表型谱。同时,我们的发现也为BMPR1A介导的JPS和CRC的未来PTC靶向治疗提供了支持.
BACKGROUND: BMPR1A-mediated signaling transduction plays an essential role in intestinal growth. Variations of BMPR1A lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the BMPR1A gene.
OBJECTIVE: This study aimed to investigate the molecular genetic etiology in a Chinese family with three generations of CRC.
METHODS: Pathogenic variants of 18 known CRC susceptibility genes were examined in a Chinese CRC family through multigene panel testing using the next-generation sequencing platform. The candidate gene variant was validated in the family members by Sanger sequencing. Potential biological functions of the gene variant were further investigated in the RKO colon cancer cell line.
RESULTS: A novel nonsense variant (c.1114A > T, p.Lys372*) of BMPR1A was identified in the CRC family. This variant generated a PTC at the kinase domain and caused nonsense-mediated mRNA decay. Read-through inducing reagents G418 and PTC124 partially restored BMPR1A expression and its following signaling pathway.
CONCLUSIONS: The identification of the novel BMPR1A variant enriched the genotype-phenotype spectrum of BMPR1A. Meanwhile, our finding also provided support for future PTC-targeting therapy for BMPR1A-mediated JPS and CRC.