CONICET | Buscador de Institutos y Recursos Humanos

Introduction: Iodide transport defect (ITD) is an autosomal recessive disorder whose hallmark is the inability of the thyroidfollicular cell to actively accumulate iodide. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism thatresults from inactivating mutations in the sodium iodide symporter (NIS)-coding gene. Clinical manifestations include low toabsent iodide accumulation in the thyroid tissue and, if untreated, the patients develop a variable degree of hypothyroidism,goiter, and even mental retardation. Objectives: The objective of this work was to investigate the presence of inactivatingmutations in the gene encoding NIS in two unrelated pediatric patients with a clinical phenotype of ITD. Methods: Thegenomic DNA encoding all fifteen NIS-coding gene exons were PCR-amplified and further subjected to Sanger sequencing.Moreover, bioinformatics analysis of the newly identified NIS variants was performed using the software Alamut. Results andconclusions: We identify two homozygous variants in the DNA sequence encoding NIS in two unrelated pediatric patientswith dyshormonogenetic congenital hypothyroidism. The patients were homozygous for the variants c.1673A>C in exon 11and c.1973C>T in exon 13, respectively. Significantly, both variants were silent but not observed in the genome of 50 healthycontrols, and therefore classified as variants of unknown clinical significance. Bioinformatics analysis revealed that both variantsare potentially deleterious for normal NIS mRNA splicing to maintain the open reading frame. The variant c.1673A>C wouldresult in the disruption of a splicing enhancer located in exon 11 and retention of intron 11, originating the putative mutantp.P443fsX86 NIS. Whereas c.1973C>T would result in a novel splicing silencer in exon 13 and retention of intron 13, originatingthe putative mutant T550fsX3 NIS. Future experiments using functional in vivo mini-gene splicing assays are requiredto fully characterize the impact of the variants on splicing defects. In conclusion, we identified two novel NIS variants of unknownclinical significance associated with dyshormonogenetic congenital hypothyroidism. These variants may lead to potentialmis-splicing defects causing structural changes in NIS molecules that impair its normal biogenesis and activity, thus leading tocongenital hypothyroidism.