Novel Sodium/Iodide Symporter Compound Heterozygous Pathogenic Variants Causing Dyshormonogenic Congenital Hypothyroidism

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

THYROID

MARY ANN LIEBERT INC

Año: 2019

1050-7256

Background:Iodide transport defect (ITD) is an autosomal recessive disorder caused by deficientiodide accumulation into the thyroid follicular cell. ITD is an uncommon causeof dyshormonogenetic congenital hypothyroidism that results from inactivatingmutations in the sodium/iodide symporter (NIS)-coding SLC5A5 gene. NIS is a key basolateral plasma membrane glycoproteinthat efficiently mediates active iodide uptake in the thyroid?constituting thefirst step in the biosynthesis of the iodine-containing thyroid hormones?andother tissues, including salivary glands, lactating breast, and smallintestine.PatientFindings: The proposita, a 20-day-old female born in 1992,was diagnosed with congenital hypothyroidism through newborn screening. ITD wassuspected on the basis of non-detectable radioiodide accumulation in a normallylocated, non-goitrous thyroid gland, as well as in salivary glands. Summary:Sanger sequencing revealed non-previously reported compound heterozygousmissense SLC5A5 gene variants (c.991G>A,p.D331N and c.1.641C>A, p.S547R). Notably, these variants have not beenreported in public databases (i.e. Exome Aggregation Consortium, 1000 Genomes,and Single Nucleotide Polymorphism). Insilico analysis using prediction softwares (i.e. SIFT, Polyphen-2, andMutationTaster2) support the pathologic significance of p.D331N and p.S547R NIS.Moreover, functional in vitro studies demonstrate that D331Nand S547R NIS severely reduce iodide uptake when the proteins areheterologously expressed in HEK-293T cells because of a pronounced impairment ofD331N and S547R NIS targeting to the plasma membrane. Of note, a chargedresidue at position 331 and a serine residue at position 547?which are highlyconserved in SLC5A family members?are required for NIS plasma membranetargeting.Conclusions:We report two novel missense pathogenic variants in a compound heterozygousstate in the SLC5A5 gene, detectedthrough Sanger sequencing, in a pediatric female patient with dyshormonogenic congenitalhypothyroidism.