Slc5a5, also known as the sodium/iodide symporter (NIS)-coding gene, is crucial for transporting iodide into thyroid follicular cells, a key step in thyroid hormone synthesis [1,2,3,4,5,6,7,8]. This process is integral to the thyroid-pituitary axis pathway, which is essential for maintaining normal physiological functions in the body. Genetic models, such as those studying gene variants, can provide insights into its function [1,4,5,6,7].

Mutations in Slc5a5 can lead to various thyroid-related disorders. Loss-of-function variants in this gene are associated with congenital iodide transport defect (ITD), a cause of dyshormonogenic congenital hypothyroidism [1,5,6]. For example, a novel homozygous synonymous variant (c.1326A>C) was found to cause aberrant NIS pre-mRNA splicing, expanding the mutational landscape of Slc5a5-related congenital hypothyroidism [1]. In a Chinese patient, novel compound heterozygous mutations (p.Gly51AlafsTer45 and p.Gly421Arg) led to reduced NIS expression and impaired iodide transport function [4]. A novel missense p.G561E NIS variant reduced iodide uptake by impairing the recognition of a motif by kinesin light chain 2, affecting NIS maturation [5]. Two novel compound heterozygous SLC5A5 variants (p. [Gln263Leu]; [Gly350Asp]) in a Japanese sibling also caused negligible iodide transport capacity [6].

In conclusion, Slc5a5 is essential for thyroid hormonogenesis through its role in iodide transport. Studies on gene variants in this gene have revealed its significance in congenital hypothyroidism and other thyroid-related diseases. Understanding the function of Slc5a5 through genetic models contributes to a better understanding of the molecular mechanisms underlying these diseases, potentially guiding future diagnostic and therapeutic strategies.

References:

1. Geysels, Romina Celeste, Bernal Barquero, Carlos Eduardo, Martín, Mariano, Miras, Mirta Beatriz, Nicola, Juan Pablo. 2022. Silent but Not Harmless: A Synonymous SLC5A5 Gene Variant Leading to Dyshormonogenic Congenital Hypothyroidism. In Frontiers in endocrinology, 13, 868891. doi:10.3389/fendo.2022.868891. https://pubmed.ncbi.nlm.nih.gov/35600585/

2. Hoang, Tung, Lee, Eun Kyung, Lee, Jeonghee, Hwangbo, Yul, Kim, Jeongseon. 2022. Seaweed and Iodine Intakes and SLC5A5 rs77277498 in Relation to Thyroid Cancer. In Endocrinology and metabolism (Seoul, Korea), 37, 513-523. doi:10.3803/EnM.2021.1306. https://pubmed.ncbi.nlm.nih.gov/35607818/

3. Oh, Ji Min, Ahn, Byeong-Cheol. 2021. Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS. In Theranostics, 11, 6251-6277. doi:10.7150/thno.57689. https://pubmed.ncbi.nlm.nih.gov/33995657/

4. Zhang, Cao-Xu, Zhang, Jun-Xiu, Yang, Liu, Li, Rui, Song, Huai-Dong. 2021. Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient With Congenital Hypothyroidism. In Frontiers in endocrinology, 12, 620117. doi:10.3389/fendo.2021.620117. https://pubmed.ncbi.nlm.nih.gov/33815280/

5. Martín, Mariano, Modenutti, Carlos Pablo, Gil Rosas, Mauco Lucas, Martí, Marcelo Adrián, Nicola, Juan Pablo. . A Novel SLC5A5 Variant Reveals the Crucial Role of Kinesin Light Chain 2 in Thyroid Hormonogenesis. In The Journal of clinical endocrinology and metabolism, 106, 1867-1881. doi:10.1210/clinem/dgab283. https://pubmed.ncbi.nlm.nih.gov/33912899/

6. Abe, Kiyomi, Koizumi, Mikiko, Kogai, Takahiko, Hasegawa, Tomonobu, Narumi, Satoshi. 2025. Two Novel SLC5A5 Variants (Q263L and G350D) Causing Congenital Hypothyroidism. In Thyroid : official journal of the American Thyroid Association, 35, 335-337. doi:10.1089/thy.2024.0716. https://pubmed.ncbi.nlm.nih.gov/39895319/

7. Stoupa, Athanasia, Al Hage Chehade, Ghada, Kariyawasam, Dulanjalee, Polak, Michel, Carré, Aurore. . First case of fetal goitrous hypothyroidism due to SLC5A5/NIS mutations. In European journal of endocrinology, 183, K1-K5. doi:10.1530/EJE-20-0255. https://pubmed.ncbi.nlm.nih.gov/32805706/

8. Stathatos, Nikolaos. 2012. Thyroid physiology. In The Medical clinics of North America, 96, 165-73. doi:10.1016/j.mcna.2012.01.007. https://pubmed.ncbi.nlm.nih.gov/22443969/