Thyroid Biology and Disease

ORF12-04 - Genetic Variants in the N-Degron Pathway Gene NTAN1 Destabilize Protein Structure: Potential Biomarkers in Thyroid Cancer

Saturday, June 13, 2026

2:00 PM - 2:15 PM CT

Location: Room W180

Oral Abstract Presenter(s)

Bruno C. R Cateb, Medical Student

Campinas, Sao Paulo, BRAZIL

Co-Author(s)

Bruno C. R Cateb, Medical Student

Campinas, Sao Paulo, BRAZIL
KP

Karina C. Peres, Researcher

Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas/SP, Brazil
Campinas, Sao Paulo, Brazil
ET

Elisangela S. Teixeira, Doctoral student

Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas/SP, Brazil
Campinas, Sao Paulo, Brazil

Senior Author/Primary Investigator(s)

NB

Natassia E. Bufalo, Researcher

Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas/SP, Brazil
Campinas, Sao Paulo, Brazil

Co-Author(s)

NB

Natassia E. Bufalo, Researcher

Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas/SP, Brazil
Campinas, Sao Paulo, Brazil

Senior Author/Primary Investigator(s)

LW

Laura S. Ward, Full Professor

Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas/SP, Brazil
Campinas, Sao Paulo, Brazil

Co-Author(s)

LW

Laura S. Ward, Full Professor

Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas/SP, Brazil
Campinas, Sao Paulo, Brazil

Disclosure(s):

Bruno C. R Cateb, Medical Student: No financial relationships to disclose

The global incidence of thyroid cancer (TC) is increasing, predominantly papillary thyroid carcinoma (PTC). The N-terminal asparagine amidase (NTAN1) gene is crucial for proteolysis via the N-degron pathway; however, the impact of its genetic polymorphisms on TC susceptibility and progression is unclear. As dysregulated proteolysis underpins thyroid malignancies, defining the functional effects of NTAN1 single nucleotide polymorphisms (SNPs) is essential for assessing their utility as biomarkers. Using dbSNP, Ensembl, and 20 bioinformatic tools such as PredictSNP2.0 (CADD, DANN, FunSeq2, FATHMM and GWAVA) and PredictSNP1.0 (SIFT, Poly-Phen1, Poly-Phen2, PhDSNP, nsSNPanalyzer, MAPP and Panther), MuPRO, NetSurf, ConSurf, NetPhos, and NetOGlyc, we screened 10,470 NTAN1 variants. After applying a minor allele frequency (MAF) filter >0.1 and removing duplicates, 37 SNPs (70 alterations) were retained for further evaluation. Regulatory and missense polymorphisms that met the MAF threshold were prioritized for detailed analysis. Analysis identified three regulatory SNPs (rs11075253, rs1135999-A/C, and rs2280017) as 50.0% deleterious, suggesting an impact on gene expression. Rs1136001 (H283Y/D/A) was classified as neutral by PredictSNP, yet it induced a novel interaction with PHE286 and reduced stability (MuPRO ΔΔG = -0.8407 to -1.1843). For rs1135999, the A>C (S287A) and A>G (S287P) substitutions were 50.0% and 33.3% deleterious, respectively, both decreasing stability (ΔΔG = -0.8679, -0.9974). Position 287 is an exposed PKC (NetPhos=0.877) and O-glycosylation site (NetOGlyc=0.2733).
Our analysis identified five NTAN1 polymorphisms with predicted deleterious effects on protein stability and regulatory function, consistent with the role of protein quality control pathways in oncogenesis. Crucially, variants at exposed residues 283 and 287 affect the stability and key post-translational modification sites, directly implicating N-degron pathway dysregulation in thyroid tumorigenesis. These findings nominate specific NTAN1 variants as candidate biomarkers, warranting future clinical validation for thyroid cancer risk and prognosis assessment in patients.