Functional characterization of novel compound heterozygous missense gene variants causing congenital dyshormonogenic hypothyroidism.

Introduction: The sodium/iodide symporter (NIS) mediates active iodide accumulation in the thyroid follicular cell. Biallelic loss-of-function variants in the NIS-coding gene cause congenital dyshormonogenic hypothyroidism due to a defect in the accumulation of iodide, which is required for thyroid hormonogenesis.

Objective: We aimed to identify, and if so to functionally characterize, novel pathogenic gene variants in a patient diagnosed with severe congenital dyshormonogenic hypothyroidism characterized by undetectable radioiodide accumulation in a eutopic thyroid gland, as well as in the salivary glands.

TIM3 Expression in Anaplastic-Thyroid-Cancer-Infiltrating Macrophages: An Emerging Immunotherapeutic Target.

Anaplastic thyroid cancer (ATC) is a clinically aggressive form of undifferentiated thyroid cancer with limited treatment options. Immunotherapy for patients with ATC remains challenging. Tumor-associated macrophages (TAMs) constitute over 50% of ATC-infiltrating cells, and their presence is associated with a poor prognosis.

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect.

Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.

Silent but Not Harmless: A Synonymous Gene Variant Leading to Dyshormonogenic Congenital Hypothyroidism.

Background: Congenital iodide transport defect (ITD) is an uncommon cause of dyshormonogenic congenital hypothyroidism characterized by the absence of active iodide accumulation in the thyroid gland. ITD is an autosomal recessive disorder caused by loss-of-function variants in the sodium/iodide symporter (NIS)-coding gene.

Objective: We aimed to identify, and if so to functionally characterize, novel ITD-causing gene variants in a cohort of five unrelated pediatric patients diagnosed with dyshormonogenic congenital hypothyroidism with minimal to absent Tc-pertechnetate accumulation in the thyroid gland.

An Intramolecular Ionic Interaction Linking Defective Sodium/Iodide Symporter Transport to the Plasma Membrane and Dyshormonogenic Congenital Hypothyroidism.

The sodium/iodide symporter (NIS) mediates active iodide accumulation in the thyroid follicular cell. Autosomal recessive iodide transport defect (ITD)-causing loss-of-function NIS variants lead to dyshormonogenic congenital hypothyroidism due to deficient iodide accumulation for thyroid hormonogenesis. Here, we aimed to identify, and if so to functionally characterize, novel ITD-causing NIS pathogenic variants in a patient diagnosed with severe dyshormonogenic congenital hypothyroidism due to a defect in iodide accumulation in the thyroid follicular cell, as suggested by nondetectable radioiodide accumulation in a normally located thyroid gland, as well as in salivary glands.

Secreted Factors by Anaplastic Thyroid Cancer Cells Induce Tumor-Promoting M2-like Macrophage Polarization through a TIM3-Dependent Mechanism.

Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most evident cells in ATCs, and their high density is correlated with a poor prognosis.

The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane.

The sodium/iodide symporter (NIS) expresses at the basolateral plasma membrane of the thyroid follicular cell and mediates iodide accumulation required for normal thyroid hormonogenesis. Loss-of-function NIS variants cause congenital hypothyroidism due to impaired iodide accumulation in thyroid follicular cells underscoring the significance of NIS for thyroid physiology. Here we report novel findings derived from the thorough characterization of the nonsense NIS mutant p.

A Novel SLC5A5 Variant Reveals the Crucial Role of Kinesin Light Chain 2 in Thyroid Hormonogenesis.

Context: Iodide transport defect (ITD) (Online Mendelian Inheritance in Man No. 274400) is an uncommon cause of dyshormonogenic congenital hypothyroidism due to loss-of-function variants in the SLC5A5 gene, which encodes the sodium/iodide symporter (NIS), causing deficient iodide accumulation in thyroid follicular cells.

Objective: This work aims to determine the molecular basis of a patient's ITD clinical phenotype.

The Transcription Factor NF-κB Mediates Thyrotropin-Stimulated Expression of Thyroid Differentiation Markers.

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor is a key regulator of cell survival, proliferation, and gene expression. Although activation of NF-κB signaling in thyroid follicular cells after thyrotropin (TSH) receptor (TSHR) engagement has been reported, the downstream signaling leading to NF-κB activation remains unexplored. Here, we sought to elucidate the mechanisms that regulate NF-κB signaling activation in response to TSH stimulation.

Novel Sodium/Iodide Symporter Compound Heterozygous Pathogenic Variants Causing Dyshormonogenic Congenital Hypothyroidism.

Iodide transport defect (ITD) is an autosomal recessive disorder caused by deficient iodide accumulation into the thyroid follicular cell. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism that results from inactivating mutations in the sodium/iodide symporter (NIS)-coding gene. NIS is a key basolateral plasma membrane glycoprotein that efficiently mediates active iodide uptake in the thyroid-constituting the first step in the biosynthesis of the iodine-containing thyroid hormones-and other tissues, including salivary glands, lactating breast, and small intestine.

Implications of Na/I Symporter Transport to the Plasma Membrane for Thyroid Hormonogenesis and Radioiodide Therapy.

Iodine is a crucial component of thyroid hormones; therefore, a key requirement for thyroid hormone biosynthesis is that iodide (I) be actively accumulated in the thyroid follicular cell. The ability of the thyroid epithelia to concentrate I is ultimately dependent on functional Na/ I symporter (NIS) expression at the plasma membrane. Underscoring the significance of NIS for thyroid physiology, loss-of-function mutations in the NIS-coding gene cause an I transport defect, resulting in dyshormonogenic congenital hypothyroidism.

A Carboxy-Terminal Monoleucine-Based Motif Participates in the Basolateral Targeting of the Na+/I- Symporter.

The Na+/iodide (I-) symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I- accumulation for thyroid hormonogenesis and radioiodide therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit lower I- transport than normal thyroid tissue (or even undetectable I- transport). Paradoxically, the majority of differentiated thyroid cancers show intracellular NIS expression, suggesting abnormal targeting to the plasma membrane.