Impact of the mutational landscape of the sodium/iodide symporter in congenital hypothyroidism

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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