AUTHOR=Carro Gerardo Hernán , Martín Mariano , Savy Sofía , Peyret Victoria , Geysels Romina Celeste , Montes Francisco Andrés , Bernal Barquero Carlos Eduardo , Ricci Valentina , Masnata María Eugenia , Masini-Repiso Ana María , Papendieck Patricia , Tellechea Mariana Lorena , Chiesa Ana Elena , Nicola Juan Pablo TITLE=Functional characterization of novel compound heterozygous missense SLC5A5 gene variants causing congenital dyshormonogenic hypothyroidism JOURNAL=Frontiers in Endocrinology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1465176 DOI=10.3389/fendo.2024.1465176 ISSN=1664-2392 ABSTRACT=Introduction

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.

Objective

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.

Methods

The coding region of the SLC5A5 gene was sequenced using whole-exome sequencing. In silico analysis and in vitro functional characterization of missense SLC5A5 gene variants were performed.

Results

Proposita’s whole-exome 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.

Conclusions

We report novel compound heterozygous missense SLC5A5 gene variants causing defective iodide accumulation, thus leading to congenital dyshormonogenic hypothyroidism.