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ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Thyroid Endocrinology
Volume 15 - 2024 |
doi: 10.3389/fendo.2024.1465176
Functional Characterization of Novel Compound Heterozygous Missense SLC5A5 Gene Variants Causing Congenital Dyshormonogenic Hypothyroidism
Provisionally accepted- 1 National University of Cordoba, Córdoba, Argentina
- 2 Hospital General de Niños Ricardo Gutierrez, Buenos Aires, Buenos Aires, Argentina
The sodium/iodide symporter (NIS) mediates active iodide accumulation in the thyroid follicular cell. Biallelic loss-of-function variants in the NIS-coding SLC5A5 gene cause congenital dyshormonogenic hypothyroidism due to a defect in the accumulation of iodide, which is required for thyroid hormonogenesis. Here, we aimed to identify, and if so to functionally characterize, novel pathogenic SLC5A5 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. Proposita's wholeexome sequencing revealed a novel pair of compound heterozygous missense variants in the SLC5A5 gene, c.1,627G>A (p.G543R) and c.1,684T>A (p.L562M). The parents were heterozygous carriers of the variants as determined by Sanger sequencing of the SLC5A5 gene.The p.G543R variant in the homozygous state has previously been associated with congenital hypothyroidism. The novel p.L562M variant was not reported in the Genome Aggregation Consortium dataset. In silico analysis of the pathogenic impact of the p.L562M variant yielded inconclusive results. Functional in vitro studies showed that the p.L562M variant reduces iodide accumulation due to defective expression of the mutant NIS protein at the plasma membrane.Notably, the aliphatic residue Leu at position 562 in the carboxy terminus of the protein, which is highly conserved in NIS orthologues, is required for NIS plasma membrane expression. In conclusion, we report novel compound heterozygous missense SLC5A5 gene variants causing defective iodide accumulation, thus leading to congenital dyshormonogenic hypothyroidism.
Keywords: Congenital Hypothyroidism, Iodide transport defect, Sodium iodide symporter (NIS), Whole-exome sequencing, Biallelic loss-of-function SLC5A5 variants
Received: 15 Jul 2024; Accepted: 04 Nov 2024.
Copyright: © 2024 Carro, MARTIN, Savy, Peyret, Geysels, Montes, Barquero, Ricci, Masnata, Masini Repiso, Papendieck, Tellechea, CHIESA and Nicola. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Juan P. Nicola, National University of Cordoba, Córdoba, Argentina
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