Nonsense suppression induces read-through of a novel BMPR1A variant in a Chinese family with hereditary colorectal cancer

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.Conclusion: 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.