Resistance to thyroid hormone beta coexisting with papillary thyroid carcinoma-two case reports of a thyroid hormone receptor beta gene mutation and a literature review.

Resistance to thyroid hormone beta (RTHß) is an autosomal dominant hereditary disorder that is difficult to diagnose because of its rarity and variable clinical features, which are caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies have indicated a close association between THRB mutations and human cancers, but the mechanistic role of THRB mutations in carcinogenesis is unknown. Herein, we report two cases of RTHß coexisting with papillary thyroid carcinoma (PTC) and their follow-up results. Two female patients presented with elevated serum thyroid hormone levels and nonsuppressed thyrotropin (TSH). Genetic analysis showed that each patient had a THRB gene mutation (p.P453T and p. R320H). Based on the results of ultrasound-guided fine-needle aspiration biopsy, the thyroid nodules were suspected to be PTC. Intraoperative pathology confirmed that the two patients had PTC with multifocal carcinoma of both lobes. One patient underwent total thyroidectomy and central lymph node dissection, and the other underwent total thyroidectomy alone. Following surgery, large doses of levothyroxine were administered to suppress TSH levels and prevent recurrent or persistent disease. However, it is difficult to continually suppress TSH levels below the upper limit of the normal range. To date, the two patients have experienced no recurrence of PTC on ultrasound.

Histological, functional and transcriptomic alterations in the juvenile hippocampus in a mouse model of thyroid hormone resistance.

Background: Proper thyroid hormone signaling via the TRα1 nuclear receptor is required for normal neurodevelopmental processes. The specific downstream mechanisms mediated by TRα1 that impact brain development remain to be investigated. Methods: In this study, the structure, function and transcriptome of hippocampal tissue in a mouse model expressing the first RTHα mutation discovered in a patient, THRA E403X, were analyzed. RNAscope was used to visualize the spatial and temporal expression of Thra1 mRNA in the hippocampus of WT mice, which is corresponding to THRA1 mRNA in humans. The morphological structure was analyzed by Nissl staining, and the synaptic transmission was analyzed on the basis of long-term potentiation. The Morris water maze test and the zero maze test were used to evaluate the behavior. RNA-seq and quantitative real-time PCR were used to analyze the differentially expressed genes (DEGs) of the hippocampal tissues in the mouse model expressing the Thra E403X mutation. Results: The juvenile mutant Thra E403X mice presented with delayed neuronal migration, disordered neuronal distribution, and decreased synaptic plasticity. A total of 754 DEGs, including 361 upregulated genes and 393 downregulated genes, were identified by RNA-seq. DEG-enriched Gene Ontology (GO) and KEGG pathways were associated with PI3K-Akt signaling, ECM-receptor interaction, neuroactive ligand-receptor interaction, and a range of immune-related pathways. 25 DEGs were validated by qPCR. Conclusions: The ThraE403X mutation results in histological and functional abnormalities, as well as transcriptomic alterations in the juvenile mouse hippocampus. This study of the ThraE403X mutant offers new insights into the biological cause of RTHα-associated neurological diseases.

lnc TINCR induced by NOD1 mediates inflammatory response in 3T3-L1 adipocytes.

OBJECTIVE: Investigating the expression of the lnc RNAs screened above between normal and insulin resistant 3T3-L1 adipocytes. Addressing the mechanism underlying the regulation of inflammation response by lnc TINCR. METHODS: 3T3-L1 preadipocytes were induced to differentiate into mature adipocytes. Oil red O staining was used to find the fat droplets in mature adipocytes. Mature adipocytes were randomized to normal control group and Tri-DAP (NOD1 ligand) group. After the establishment of insulin resistance model, we used deep RNA sequencing(RNA-Seq) to identify lncRNAs that are regulated during NODI activation in mouse adipocytes. Real-time PCR was used to analyze the expression of lnc TINCR, proinflammatory IL-6, TNF-α, Cxcl1 and RIPK2 in the presence or absence of Tri-DAP(10 µg/ml). We employed siRNA against lnc TINCR to confirm its effects in inflammatory response. RESULTS: Deep RNA sequencing identified 81 lncRNAs and 167 coding genes that were significantly up-related while 78 lncRNAs and 82 coding genes that were significantly down-related greater than twofold during NOD1 activation in adipocytes. We discovered that lnc TINCR, termed lnc TINCR(Tri-DAP-inducible non-protein coding RNA) is greatly upregulated in Tri-DAP activated adipocytes. Moreover knockdown of lnc TINCR dampens the proinflammatory response (P < 0.05; in adipocytes). CONCLUSIONS: lnc TINCR is a positive regulator of inflammation-induced insulin resistance presumably via activation of NOD1 signaling pathways.