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

MARTÍN, M; ; BERNAL BARQUERO, C; GEYSELS, R; ; PAPENDIECK, P;; PEYRET, V; MASINI-REPISO, A; CHIESA, A; ; NICOLA,J

THYROID

MARY ANN LIEBERT INC

Lugar: New York; Año: 2019 vol. 29 p. 1023 - 1026

1050-7256

Iodide transport defect (ITD) is an autosomal recessive disorder caused by deficient iodide accumulation intothe thyroid follicular cell. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism thatresults from inactivating mutations in the sodium/iodide symporter (NIS)-coding SLC5A5 gene. NIS is a keybasolateral plasma membrane glycoprotein that efficiently mediates active iodide uptake in the thyroid?constituting the first step in the biosynthesis of the iodine-containing thyroid hormones?and other tissues,including salivary glands, lactating breast, and small intestine. The proposita, a 20-day-old female born in 1992,was diagnosed with congenital hypothyroidism through newborn screening. ITD was suspected on the basis ofnondetectable radioiodide accumulation in a normally located nongoitrous thyroid gland, as well as in salivaryglands. Sanger sequencing revealed nonpreviously reported compound heterozygous missense SLC5A5 genevariants (c.991G>A, p.D331N and c.1.641C>A, p.S547R). Notably, these variants have not been reported inpublic databases (i.e., Exome Aggregation Consortium, 1000 Genomes, and Single Nucleotide Polymorphism).In silico analysis using prediction softwares (i.e., SIFT, Polyphen-2, and MutationTaster2) support the pathologicsignificance of p.D331N and p.S547R NIS. Moreover, functional in vitro studies demonstrate that D331Nand S547R NIS severely reduce iodide uptake when the proteins are heterologously expressed in HEK-293Tcells because of a pronounced impairment of D331N and S547R NIS targeting to the plasma membrane. Ofnote, a charged residue at position 331 and a serine residue at position 547?which are highly conserved inSLC5A family members?are required for NIS plasma membrane targeting. We report two novel missensepathogenic variants in a compound heterozygous state in the SLC5A5 gene, detected through Sanger sequencing,in a pediatric female patient with dyshormonogenic congenital hypothyroidism.