Novel mutations in the Na+/I- symporter-coding SLC5A5 gene in a patient with dyshormonogenic congenital hypothyroidism

GEYSELS, RC; PAPENDIECK, P; NICOLA, JP; MARTIN, M; MASINI-REPISO, AM; BERNAL BARQUERO, CE; PEYRET, V; CHIESA, AE

Buenos Aires

Congreso; XVII Latin American Thyroid Society Congress; 2019

Latin American Thyroid Society

Dyshormonogenic congenitalhypothyroidism is caused by inactivating mutations in genes involved in thyroidhormonogenesis. Mutations in the Na+/I- symporter (NIS)-coding SLC5A5 gene cause an autosomal recessivedisorder known as iodide transport defect (ITD), due to impaired thyroidal iodideaccumulation.Tostudy a pediatric patient diagnosed with congenital hypothyroidism suspected ofITD on the basis of non-detectable radioiodide accumulation in a eutopic thyroidgland.Thenucleotide sequence encoding the SLC5A5gene was studied using Sanger sequencing. Insilico computational and in vitrofunctional studies of novel NIS mutants were performed.Weidentified novel compound heterozygous SLC5A5variants (c.967C>A, p.Q323K and c.1.106A>T, p.D369V) non-annotated inpublic databases (i.e. ExAc, 1000 genomes, and dbSNP). In silico analysis using prediction softwares (i.e. SIFT,Polyphen-2, and MutationTaste2) support the pathologic significance of Q323Kand D369V NIS. Functional in vitrostudies revealed that D369V NIS was associated with non-detectable iodideaccumulation when transiently transfected into HEK-293T cells, which do notexpress NIS endogenously. The NIS variant Q323K has not been tested yet. Immunofluorescenceand immunoblot analysis evidenced that D369V NIS is fully retained in theendoplasmic reticulum and, therefore do not reach the plasma membrane. Of note,a negatively charged residue at position 369?a highly conserved residue inSLC5A family members?is required for NIS transport to the plasma membrane.Wereport novel missense pathogenic variants in a compound heterozygous state inthe SLC5A5 gene in a pediatricpatient with dyshormonogenic congenital hypothyroidism.