NOVEL MUTATIONS IN THE NA+/I- SYMPORTER-CODING SLC5A5 GENE IN A PATIENT WITH DYSHORMONOGENIC CONGENITAL HYPOTHYROIDISM

Buenos Aires

Congreso; XVII Latin American Thyroid Congress; 2019

Sociedad Latinoamericana de Tiroides

Introduction: Dyshormonogenic congenital hypothyroidism is caused by inactivating mutations in genes involved in thyroidhormonogenesis. Mutations in the Na+/I- symporter (NIS)-coding SLC5A5 gene cause an autosomal recessive disorder known asiodide transport defect (ITD), due to impaired thyroidal iodide accumulation. Objectives: To study a pediatric patient diagnosedwith congenital hypothyroidism suspected of ITD on the basis of non-detectable radioiodide accumulation in a eutopic thyroid gland.Methods: The nucleotide sequence encoding the SLC5A5 gene was studied using Sanger sequencing. In silico computational and invitro functional studies of novel NIS mutants were performed. Results: We identified novel compound heterozygous SLC5A5 variants(c.967C>A, p.Q323K and c.1.106A>T, p.D369V) non-annotated in public databases (i.e. ExAc, 1000 genomes, and dbSNP). Insilico analysis using prediction softwares (i.e. SIFT, Polyphen-2, and MutationTaste2) support the pathologic significance of Q323Kand D369V NIS. Functional in vitro studies revealed that D369V NIS was associated with non-detectable iodide accumulation whentransiently transfected into HEK-293T cells, which do not express NIS endogenously. The NIS variant Q323K has not been tested yet.Immunofluorescence and immunoblot analysis evidenced that D369V NIS is fully retained in the endoplasmic reticulum and, thereforedo not reach the plasma membrane. Of note, a negatively charged residue at position 369 ? a highly conserved residue in SLC5A familymembers ? is required for NIS transport to the plasma membrane. Conclusion: We report novel missense pathogenic variants in acompound heterozygous state in the SLC5A5 gene in a pediatric patient with dyshormonogenic congenital hypothyroidism