Impact of the Mutational Landscape of the Sodium/Iodide Symporter in Congenital Hypothyroidism

Martín, Mariano; Nicola, Juan Pablo

doi:10.1089/thy.2021.0381

Cited by 3 publications

(2 citation statements)

References 51 publications

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“…The functional characterization of loss-of-function NIS variants identified in patients has provided mechanistic information about the transporter [ 9 ]. Given the relevance of NIS in thyroid physiology, we recently developed a machine learning-based NIS-specific variant classifier with the aim of improving the prediction of the pathogenicity of missense NIS variants [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

Barquero

Geysels

Jacques

et al. 2022

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

Barquero

Geysels

Jacques

et al. 2022

IJMS

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“…Moreover, the functional characterization of the p.D396V NIS variant uncovered a critical intramolecular ionic interaction—involving the β carboxyl group of D369 and the guanidinium group of R130—for the correct folding required for NIS maturation and transport to the plasma membrane ( 11 ). Recently, based on structure-function analysis of pathogenic NIS variants, we developed a machine learning-based NIS-specific variant classifier aiming to improve the prediction of pathogenicity of missense NIS variants in clinical practice ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Silent but Not Harmless: A Synonymous SLC5A5 Gene Variant Leading to Dyshormonogenic Congenital Hypothyroidism

et al. 2022

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BackgroundCongenital iodide transport defect (ITD) is an uncommon cause of dyshormonogenic congenital hypothyroidism characterized by the absence of active iodide accumulation in the thyroid gland. ITD is an autosomal recessive disorder caused by loss-of-function variants in the sodium/iodide symporter (NIS)-coding SLC5A5 gene.ObjectiveWe aimed to identify, and if so to functionally characterize, novel ITD-causing SLC5A5 gene variants in a cohort of five unrelated pediatric patients diagnosed with dyshormonogenic congenital hypothyroidism with minimal to absent 99mTc-pertechnetate accumulation in the thyroid gland.MethodsThe coding region of the SLC5A5 gene was sequenced using Sanger sequencing. In silico analysis and functional in vitro characterization of a novel synonymous variant were performed.ResultsSanger sequencing revealed a novel homozygous synonymous SLC5A5 gene variant (c.1326A>C in exon 11). In silico analysis revealed that the c.1326A>C variant is potentially deleterious for NIS pre-mRNA splicing. The c.1326A>C variant was predicted to lie within a putative exonic splicing enhancer reducing the binding of splicing regulatory trans-acting protein SRSF5. Splicing minigene reporter assay revealed that c.1326A>C causes exon 11 or exon 11 and 12 skipping during NIS pre-mRNA splicing leading to the NIS pathogenic variants p.G415_P443del and p.G415Lfs*32, respectively. Significantly, the frameshift variant p.G415Lfs*32 is predicted to be subjected to degradation by nonsense-mediated decay.ConclusionsWe identified the first exonic synonymous SLC5A5 gene variant causing aberrant NIS pre-mRNA splicing, thus expanding the mutational landscape of the SLC5A5 gene leading to dyshormonogenic congenital hypothyroidism.

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An Intramolecular Ionic Interaction Linking Defective Sodium/Iodide Symporter Transport to the Plasma Membrane and Dyshormonogenic Congenital Hypothyroidism

Barquero

Martín

Geysels

et al. 2021

Thyroid

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Impact of the Mutational Landscape of the Sodium/Iodide Symporter in Congenital Hypothyroidism

Cited by 3 publications

References 51 publications

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

Silent but Not Harmless: A Synonymous SLC5A5 Gene Variant Leading to Dyshormonogenic Congenital Hypothyroidism

An Intramolecular Ionic Interaction Linking Defective Sodium/Iodide Symporter Transport to the Plasma Membrane and Dyshormonogenic Congenital Hypothyroidism

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