A truncated protein product of the germline variant of the gene leads to adenomatous polyposis.

OBJECTIVE

In some patients with adenomatous polyposis, an identifiable pathogenic variant of known associated genes cannot be found. Researchers have studied this for decades; however, few new genes have been identified.

METHODS

Adenomatous polyposis coli () negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification. Then, whole-exome sequencing (WES) was used to determine candidate genes harboring pathogenic variants. Functional experiments were performed to explore their effects. Subsequently, using Sanger sequencing, we found other polyposis patients carrying variants of the gene, encoding dual oxidase 2, and analyzed them.

RESULTS

From 88 patients with suspected familial adenomatous polyposis, 25 unrelated negative polyposis patients were identified. Based on the WES results of 3 patients and 2 healthy relatives from a family, the germline nonsense variant (c.1588A>T; p.K530X) of the gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis. During functional experiments, we observed that the truncated protein, hDuox2 K530, was overexpressed in the adenoma in a carrier of the nonsense variant, causing abnormal cell proliferation through endoplasmic reticulum (ER) retention. In addition, we found two unrelated negative patients carrying missense variants (c.3329G>A, p.R1110Q; c.4027C>T, p.L1343F). Given the results of the analysis, these two missense variants might exert a negative influence on the function of hDuox2.

CONCLUSIONS

To our knowledge, this is the first study that reports the possible association of germline variants with adenomatous polyposis. With an autosomal dominant inheritance, it causes ER retention, inducing an unfolded protein response.