Identification of as a Susceptibility Gene for Familial Non-Medullary Thyroid Carcinoma.

Familial non-medullary thyroid carcinoma (FNMTC) is a genetically predisposed disease with unclear genetic mechanisms. This makes research on susceptibility genes important for the diagnosis and treatment options. This study included a five-member family affected by papillary thyroid carcinoma. The candidate genes were identified through whole-exome sequencing and Sanger sequencing in family members, other FNMTC patients, and sporadic non-medullary thyroid carcinoma patients. The pathogenicity of the mutation was predicted using tools. Cell phenotype experiments and models of lung distant metastasis were conducted to confirm the characteristics of the mutation. Transcriptome sequencing and mechanistic validation were employed to compare the disparities between wild-type (WT) and mutant (MUT) cell lines. This mutation alters the protein structure, potentially increasing instability by affecting hydrophobicity, intra-molecular hydrogen bonding, and phosphorylation sites. It specifically promotes phosphorylated PAK4 nuclear translocation and expression in thyroid tissue and cell lines. Compared with the WT cells line, I417T demonstrates enhanced proliferation, invasiveness, accelerated cell division, and inhibition of cell apoptosis . In addition, it exhibits a significant propensity for metastasis . It activates tumor necrosis factor signaling through increased phosphorylation of PAK4, JNK, NFκB, and c-Jun, unlike the WT that activates it via the PAK4-NFκ-MMP9 axis. In addition, PAK4 MUT protein interacts with matrix metalloproteinase (MMP)3 and regulates MMP3 promoter activity, which is not observed in the WT. Our study identified : c.T1250C: p.I417T as a potential susceptibility gene for FNMTC. The study concludes that the mutant form of exhibits oncogenic function, suggesting its potential as a novel diagnostic molecular marker for FNMTC.