| Title: |
Functional characterization of novel compound heterozygous missense SLC5A5 gene variants causing congenital dyshormonogenic hypothyroidism |
| Authors: |
Gerardo Hernán Carro; Mariano Martín; Sofía Savy; Victoria Peyret; Romina Celeste Geysels; Francisco Andrés Montes; Carlos Eduardo Bernal Barquero; Valentina Ricci; María Eugenia Masnata; Ana María Masini-Repiso; Patricia Papendieck; Mariana Lorena Tellechea; Ana Elena Chiesa; Juan Pablo Nicola |
| Source: |
Frontiers in Endocrinology, Vol 15 (2024) |
| Publisher Information: |
Frontiers Media S.A. |
| Publication Year: |
2024 |
| Collection: |
Directory of Open Access Journals: DOAJ Articles |
| Subject Terms: |
congenital hypothyroidism; iodide transport defect; sodium iodide symporter (NIS); whole-exome sequencing; biallelic loss-of-function SLC5A5 variants; Diseases of the endocrine glands. Clinical endocrinology; RC648-665 |
| Description: |
IntroductionThe 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.ObjectiveWe 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.MethodsThe 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.ResultsProposita’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.ConclusionsWe report novel compound heterozygous missense SLC5A5 gene variants causing defective iodide accumulation, thus leading to congenital dyshormonogenic hypothyroidism. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://www.frontiersin.org/articles/10.3389/fendo.2024.1465176/full; https://doaj.org/toc/1664-2392; https://doaj.org/article/08c0c6fe2b22458a85c98bf6187dba27 |
| DOI: |
10.3389/fendo.2024.1465176 |
| Availability: |
https://doi.org/10.3389/fendo.2024.1465176; https://doaj.org/article/08c0c6fe2b22458a85c98bf6187dba27 |
| Accession Number: |
edsbas.FB27DC2E |
| Database: |
BASE |