Document Type
Article
Publication Date
8-17-2022
Abstract
Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.
Recommended Citation
Bernal Barquero, C.E.; Geysels, R.C.; Jacques, V.; Carro, G.H.; Martín, M.; Peyret, V.; Abregú, M.C.; Papendieck, P.; Masini-Repiso, A.M.; Savagner, F.; et al. Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect. Int. J. Mol. Sci. 2022, 23, 9251. https://doi.org/10.3390/ijms23169251
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Hormones, Hormone Substitutes, and Hormone Antagonists Commons, Other Pharmacy and Pharmaceutical Sciences Commons
Comments
This article was originally published in International Journal of Molecular Sciences, volume 23, issue 16, in 2022. https://doi.org/10.3390/ijms23169251