Work

A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis

Year: 2021

Type: article

Abstract: Objective: In some patients with adenomatous polyposis, an identifiable pathogenic variant of known associated genes cannot befound. Researchers have studied this for decades; however, few new genes have been identified. Methods: Adenomatous polyposis coli (APC) negative polyposis patients were identified through next-generation sequencingand multiplex ligation-dependent probe amplification. Then, whole-exome sequencing (WES) was used to determine candidategenes harboring pathogenic variants. Functional experiments were performed to explore their effects. Subsequently, using Sangersequencing, we found other polyposis patients carrying variants of the DUOX2 gene, encoding dual oxidase 2, and analyzed them. Results: From 88 patients with suspected familial adenomatous polyposis, 25 unrelated APC negative polyposis patients wereidentified. 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 DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis. Duringfunctional experiments, we observed that the truncated protein, hDuox2 K530, was overexpressed in the adenoma in a carrier of theDUOX2 nonsense variant, causing abnormal cell proliferation through endoplasmic reticulum (ER) retention. In addition, we foundtwo unrelated APC negative patients carrying DUOX2 missense variants (c.3329G>A, p.R1110Q; c.4027C>T, p.L1343F). Given theresults of the in silico 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 DUOX2 germline variants withadenomatous polyposis. With an autosomal dominant inheritance, it causes ER retention, inducing an unfolded protein response.

Source: Cancer Biology and Medicine

DOI: 10.20892/j.issn.2095-3941.2020.0305