Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient With Congenital Hypothyroidism.

Cao-Xu Zhang,Feng Cheng,Chang-Run Zhang,Pei-Zhang Li,Jun-Xiu Zhang,Rui Li,Feng-Yao Wu,Rui-Jia Zhang,Liu Yang,Ya Fang,Huai-Dong Song,Jun Liang,Zheng Wang

doi:10.3389/fendo.2021.620117

Abstract

Background and ObjectivesDefects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation.MethodsTwo hundred and seventy-three patients with primary CH were screened for mutations in SLC5A5 using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in SLC5A5. The functional activity of the mutants was further examined in vitro.ResultsIn 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in SLC5A5 were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. In vitro experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired.ConclusionThe undescribed compound heterozygous mutation of SLC5A5 was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of SLC5A5 in CH pathogenesis.

Highlights

Congenital hypothyroidism (CH), which is defined by inadequate thyroid hormone production in newborn infants, is a common neonatal endocrine disorder with the incidence at about 1:2,000– 4,000 worldwide [1]
We report a novel compound heterozygous missense mutation G51fs/G421R of SLC5A5 gene in a pediatric patient diagnosed as congenital hypothyroidism from newborn screening
All the exons and exon-intron boundaries of SLC5A5 were amplified by performing multiplex polymerase chain reaction (PCR) using a 48×48Access ArrayTM microfluidic platform (Fluidigm) according to the manufacturer’s protocol

Summary

Introduction

Congenital hypothyroidism (CH), which is defined by inadequate thyroid hormone production in newborn infants, is a common neonatal endocrine disorder with the incidence at about 1:2,000– 4,000 worldwide [1]. The human SLC5A5 (GenBank reference sequence: NM_000453.3) gene, encoding the sodium-iodide symporter (NIS), a 643 amino acid protein, is located on chromosome 19 and consists of 15 exons [3]. Several iodine transport defect-related mutations of SLC5A5 have been identified, including G18R, V59E, G93R, R124H, Q267E, V270E, C272X, D331N, Y348D, T354P, G395R, R516X, G543E, and S547R, which have provided valuable structural evidence about the symporter and helped us to understand the pathogenesis of this disease [11,12,13,14,15,16,17,18,19,20,21,22,23,24]. Defects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation

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Discussion

Conclusion