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

Martín, Mariano; Barquero, Carlos Eduardo Bernal; Geysels, Romina C.; Papendieck, Patricia; Peyret, Victoria; Masini-Repiso, Ana M.; Chiesa, Ana; Nicola, Juan Pablo

doi:10.1089/thy.2019.0046

Cited by 18 publications

(10 citation statements)

References 8 publications

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“…The inactivating mutations in the SLC5A5 gene lead to deficient iodide accumulation into the thyroid follicular cells, and this is an uncommon cause of dyshormonogenetic congenital hypothyroidism. 11 …”

Section: Introductionmentioning

confidence: 99%

Combination of peroxisome proliferator–activated receptor gamma and retinoid X receptor agonists induces sodium/iodide symporter expression and inhibits cell growth of human thyroid cancer cells

Chen

Wang

Wen³

et al. 2020

Journal of the Chinese Medical Association

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Background: Thyroid tumors are the most frequent neoplasm of the endocrine system. The major treatment is surgical intervention followed by radioiodine therapy. The sodium/iodide symporter (NIS) has positive expression in thyroid carcinomas with good prognoses and plays a critical role in radioiodine therapy response. Low expression of NIS always leads to tumor recurrence or treatment failure. Redifferentiation therapy is more tumor specific than chemotherapy. Peroxisome proliferator–activated receptor gamma (PPARγ) agonists and retinoids are two types of redifferentiating agents. In this study, we examined whether the PPARγ agonist rosiglitazone and retinoid X receptor (RXR) agonist bexarotene could increase NIS expression and exhibit anticancer activity in human thyroid cancer cells. Methods: Using a TCGA data set, we analyzed the expression of NIS (SLC5A5), PPARγ, and RXR in clinical thyroid tumors and assessed their correlations with the relapse-free survival (RFS) of thyroid tumor patients. Moreover, two human thyroid cancer cell lines, differentiated thyroid papillary BCPAP cells and follicular follicular thyroid cancer-131 cells, were treated with different concentrations of the PPARγ agonist rosiglitazone alone or in combination with the RXR agonist bexarotene. Cell growth was analyzed by the MTT assay. NIS protein expression was determined by Western blotting. Results: From analysis of the TCGA data set, we found that thyroid tumors have lower expression of both NIS (SLC5A5) and PPARγ than nontumor controls. Higher expression levels of NIS, PPARγ, and RXR are associated with higher RFS in patients with thyroid tumors. Moreover, rosiglitazone treatment reduced cell growth and increased NIS protein expression in thyroid cancer cells under normoxic or hypoxic conditions. In addition, bexarotene potentiated the effects of rosiglitazone on cell growth and NIS protein expression. Conclusion: Our results suggest that the combination of PPARγ and RXR agonists has potential as a chemotherapeutic strategy for thyroid cancer.

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Section: Introductionmentioning

confidence: 99%

Combination of peroxisome proliferator–activated receptor gamma and retinoid X receptor agonists induces sodium/iodide symporter expression and inhibits cell growth of human thyroid cancer cells

Chen

Wang

Wen³

et al. 2020

Journal of the Chinese Medical Association

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“…MDCK cells were incubated in growth media containing 10 μM iodide supplemented with 50 μCi/μmol 125 I‐iodide (PerkinElmer) for 30 minutes at 37°C 12 . NIS‐mediated iodide uptake was assessed in the presence of 40 μM perchlorate, a competitive NIS inhibitor.…”

Section: Methodsmentioning

confidence: 99%

“…MDCK cells were incubated in growth media containing 10 μM iodide supplemented with 50 μCi/μmol 125 I-iodide (PerkinElmer) for 30 minutes at 37°C. 12 NIS-mediated iodide uptake was assessed in the presence of 40 μM perchlorate, a competitive NIS inhibitor. Accumulated radioiodide was extracted with ice-cold ethanol and then quantified in a Triathler Gamma Counter (Hidex).…”

Section: Iodide Transport Assaysmentioning

confidence: 99%

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

et al. 2021

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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.R636* NIS-leading to a truncated protein missing the last eight amino acids-identified in twins with congenital hypothyroidism. R636* NIS is severely mislocalized into intracellular vesicular compartments due to the lack of a conserved carboxy-terminal type 1 PDZ-binding motif. As a result, R636* NIS is barely targeted to the plasma membrane and therefore iodide transport is reduced. Deletion of the PDZ-binding motif causes NIS accumulation into late endosomes and lysosomes. Using PDZ domain arrays, we revealed that the PDZ-domain containing protein SCRIB binds to the carboxy-terminus of NIS by a PDZ-PDZ interaction. Furthermore, in CRISPR/Cas9based SCRIB deficient cells, NIS expression at the basolateral plasma membrane is compromised, leading to NIS localization into intracellular vesicular compartments.We conclude that the PDZ-binding motif is a plasma membrane retention signal that participates in the polarized expression of NIS by selectively interacting with the PDZ-domain containing protein SCRIB, thus retaining the transporter at the basolateral plasma membrane. Our data provide insights into the molecular mechanisms that regulate NIS expression at the plasma membrane, a topic of great interest in the 2 of 13 | MARTÍN eT Al.

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“…NIS is the principal molecule responsible for iodide uptake in the mammary gland playing a pivotal role in iodide concentration in breast milk ( 67 , 82 ) ( Figure 2 ). Eighteen NIS mutations have been reported in the Slc5a5 , the gene that encodes for NIS ( 30 , 83 , 84 ). The type of mutations in Slc5a5 includes nonsense, alternative splicing, frameshift, deletion, and missense, and they are responsible for causing ITD ( 20 ).…”

Section: Nis Variants That Affect Iodide Concentration In Breast Milkmentioning

confidence: 99%

Thyroid Gene Mutations in Pregnant and Breastfeeding Women Diagnosed With Transient Congenital Hypothyroidism: Implications for the Offspring’s Health

et al. 2021

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Fetus and infants require appropriate thyroid hormone levels and iodine during pregnancy and lactation. Nature endorses the mother to supply thyroid hormones to the fetus and iodine to the lactating infant. Genetic variations on thyroid proteins that cause dyshormonogenic congenital hypothyroidism could in pregnant and breastfeeding women impair the delivery of thyroid hormones and iodine to the offspring. The review discusses maternal genetic variations in thyroid proteins that, in the context of pregnancy and/or breastfeeding, could trigger thyroid hormone deficiency or iodide transport defect that will affect the proper development of the offspring.

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

Cited by 18 publications

References 8 publications

Combination of peroxisome proliferator–activated receptor gamma and retinoid X receptor agonists induces sodium/iodide symporter expression and inhibits cell growth of human thyroid cancer cells

Combination of peroxisome proliferator–activated receptor gamma and retinoid X receptor agonists induces sodium/iodide symporter expression and inhibits cell growth of human thyroid cancer cells

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

Thyroid Gene Mutations in Pregnant and Breastfeeding Women Diagnosed With Transient Congenital Hypothyroidism: Implications for the Offspring’s Health

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