An intramolecular ionic interaction linking defective sodium/iodide symporter transport to the plasma membrane and dyshormonogenic congenital hypothyroidism

Adequate iodide supply and metabolism are essential for thyroid hormones synthesis. In thyrocytes, iodide uptake is mediated by the sodium-iodide symporter, but several proteins appear to be involved in iodide efflux. Previous studies demonstrated that pendrin is able to mediate apical efflux of iodide in thyrocytes. Acute iodide excess transiently impairs thyroid hormone synthesis, a phenomenon known as the Wolff-Chaikoff effect. Although the escape from this inhibitory effect is not completely understood, it has been related to the inhibition of sodium-iodide symporter-mediated iodide uptake. However, the effects of iodide excess on iodide efflux have not been characterized. Herein, we investigated the consequences of iodide excess on pendrin abundance, subcellular localization, and iodide efflux in rat thyroid PCCl3 cells. Our results indicate that iodide excess increases pendrin abundance and plasma membrane insertion after 24 h of treatment. Moreover, iodide excess increases pendrin half-life. Finally, iodide exposure also increases iodide efflux from PCCl3 cells. In conclusion, these data suggest that pendrin may have an important role in mediating iodide efflux in thyrocytes, especially under conditions of iodide excess.

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Mutation screening of the sodium iodide symporter gene in a cohort of 105 China patients with congenital hypothyroidism

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/0004-2730000003436 ◽

2014 ◽

Vol 58 (8) ◽

pp. 828-832 ◽

Cited By ~ 3

Author(s):

Chunyun Fu ◽

Shaoke Chen ◽

Rongyu Chen ◽

Xin Fan ◽

Jingsi Luo ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Sodium Iodide ◽

Mutation Screening ◽

Gene Mutations ◽

Sodium Iodide Symporter ◽

Blood Leukocytes ◽

Autonomous Region ◽

Guangxi Zhuang Autonomous Region ◽

Missense Variation ◽

Nis Gene

Objective Dyshormonogenetic congenital hypothyroidism (CH) was reported to be associated with a mutation in the sodium iodide symporter (NIS) gene. The present study was undertaken in the Guangxi Zhuang Autonomous Region of China, to determine the nature and frequency of NIS gene mutations among patients with CH due to dyshormonogenesis. Subjects and methods: Blood samples were collected from 105 dyshormonogenetic CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the NIS gene together with their exon-intron boundaries were screened by next-generation sequencing. Results Two silent variations (T221T and T557T) and one missense variation (M435L), as well as two polymorphisms (rs200587561 and rs117626343) were found. Conclusions Our results indicate that the NIS mutation rate is very low in the Guangxi Zhuang Autonomous Region, China, and it is necessary to study mutations of other genes that have major effects on thyroid dyshormonogenesis and have not as yet been studied in this population.

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Congenital Hypothyroidism Caused by a PAX8 Gene Mutation Manifested as Sodium/Iodide Symporter Gene Defect

Journal of Thyroid Research ◽

10.4061/2010/619013 ◽

2010 ◽

Vol 2010 ◽

pp. 1-3 ◽

Cited By ~ 11

Author(s):

Wakako Jo ◽

Katsura Ishizu ◽

Kenji Fujieda ◽

Toshihiro Tajima

Keyword(s):

Thyroid Gland ◽

Congenital Hypothyroidism ◽

Sodium Iodide ◽

Present Report ◽

Sodium Iodide Symporter ◽

Loss Of Function ◽

Laboratory Findings ◽

Iodide Transport ◽

Transport Defect ◽

Pax8 Gene

Loss-of-function mutations of the PAX8 gene are considered to mainly cause congenital hypothyroidism (CH) due to thyroid hypoplasia. However, some patients with PAX8 mutation have demonstrated a normal-sized thyroid gland. Here we report a CH patient caused by a PAX8 mutation, which manifested as iodide transport defect (ITD). Hypothyroidism was detected by neonatal screening and L-thyroxine replacement was started immediately. Although I scintigraphy at 5 years of age showed that the thyroid gland was in the normal position and of small size, his iodide trapping was low. The ratio of the saliva/plasma radioactive iodide was low. He did not have goiter; however laboratory findings suggested that he had partial ITD. Gene analyses showed that the sodium/iodide symporter (NIS) gene was normal; instead, a mutation in the PAX8 gene causing R31H substitution was identified. The present report demonstrates that individuals with defective PAX8 can have partial ITD, and thus genetic analysis is useful for differential diagnosis.

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Mutations in the sodium/iodide symporter (NIS) gene as a cause for iodide transport defects and congenital hypothyroidism

Biochimie ◽

10.1016/s0300-9084(99)80097-2 ◽

1999 ◽

Vol 81 (5) ◽

pp. 469-476 ◽

Cited By ~ 41

Author(s):

Joachim Pohlenz ◽

Samuel Refetoff

Keyword(s):

Congenital Hypothyroidism ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Transport ◽

Nis Gene

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Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient With Congenital Hypothyroidism

Frontiers in Endocrinology ◽

10.3389/fendo.2021.620117 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cao-Xu Zhang ◽

Jun-Xiu Zhang ◽

Liu Yang ◽

Chang-Run Zhang ◽

Feng Cheng ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Sodium Iodide ◽

Chinese Patients ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Sodium Iodide Symporter ◽

Transmembrane Segment ◽

Pathogenic Mutations

Background and ObjectivesDefects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation.MethodsTwo hundred and seventy-three patients with primary CH were screened for mutations in SLC5A5 using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in SLC5A5. The functional activity of the mutants was further examined in vitro.ResultsIn 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in SLC5A5 were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. In vitro experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired.ConclusionThe undescribed compound heterozygous mutation of SLC5A5 was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of SLC5A5 in CH pathogenesis.

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Brief Report: A Novel Sodium/Iodide Symporter Mutation, S356F, Causing Congenital Hypothyroidism.

Thyroid ◽

10.1089/thy.2021.0478 ◽

2021 ◽

Author(s):

Harsh Durgia ◽

Adeline K. Nicholas ◽

Erik Schoenmakers ◽

Jennifer A Dickens ◽

Dhanapathi Halanaik ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Sodium Iodide ◽

Sodium Iodide Symporter

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Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein

Clinical Endocrinology ◽

10.1046/j.1365-2265.2003.01877.x ◽

2003 ◽

Vol 59 (4) ◽

pp. 500-506 ◽

Cited By ~ 18

Author(s):

Massimo Tonacchera ◽

Patrizia Agretti ◽

Giuseppina De Marco ◽

Rossella Elisei ◽

Anna Perri ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Sodium Iodide ◽

Sodium Iodide Symporter

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Na+ coordination at the Na2 site of the Na+/I− symporter

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607231113 ◽

2016 ◽

Vol 113 (37) ◽

pp. E5379-E5388 ◽

Cited By ~ 11

Author(s):

Giuseppe Ferrandino ◽

Juan Pablo Nicola ◽

Yuly E. Sánchez ◽

Ignacia Echeverria ◽

Yunlong Liu ◽

...

Keyword(s):

Plasma Membrane ◽

Binding Sites ◽

Sodium Iodide ◽

The Other ◽

Similar Function ◽

Sodium Iodide Symporter ◽

Whole Cells ◽

Thyroid Hormone Biosynthesis ◽

Hormone Biosynthesis ◽

Medical Relevance

The sodium/iodide symporter (NIS) mediates active I− transport in the thyroid—the first step in thyroid hormone biosynthesis—with a 2 Na+: 1 I− stoichiometry. The two Na+ binding sites (Na1 and Na2) and the I− binding site interact allosterically: when Na+ binds to a Na+ site, the affinity of NIS for the other Na+ and for I− increases significantly. In all Na+-dependent transporters with the same fold as NIS, the side chains of two residues, S353 and T354 (NIS numbering), were identified as the Na+ ligands at Na2. To understand the cooperativity between the substrates, we investigated the coordination at the Na2 site. We determined that four other residues—S66, D191, Q194, and Q263—are also involved in Na+ coordination at this site. Experiments in whole cells demonstrated that these four residues participate in transport by NIS: mutations at these positions result in proteins that, although expressed at the plasma membrane, transport little or no I−. These residues are conserved throughout the entire SLC5 family, to which NIS belongs, suggesting that they serve a similar function in the other transporters. Our findings also suggest that the increase in affinity that each site displays when an ion binds to another site may result from changes in the dynamics of the transporter. These mechanistic insights deepen our understanding not only of NIS but also of other transporters, including many that, like NIS, are of great medical relevance.

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