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      Congenital goitrous hypothyroidism is caused by dysfunction of the iodide transporter SLC26A7

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          Abstract

          Iodide transport and storage in the thyroid follicles is crucial for thyroid hormone synthesis. Pendrin, the iodide exporter that transports iodide to thyroid follicles, is responsible for Pendred syndrome, a disorder characterized by congenital hypothyroidism and hearing loss. However, thyroid hormone levels are basically normal in patients with Pendred syndrome, indicating the presence of another unknown iodide transporter. Here, we show that SLC26A7 is a novel iodide transporter in the thyroid. We observe that SLC26A7 is specifically expressed in normal thyroid tissues and demonstrate its function in iodide transport. Using whole-exome sequencing, we also find a homozygous nonsense mutation in SLC26A7 (c.1498 C > T; p.Gln500Ter) in two siblings with congenital goitrous hypothyroidism. The mutated SLC26A7 protein shows an abnormal cytoplasmic localisation and lacks the iodide transport function. These results reveal that SLC26A7 functions as a novel iodide transporter in the thyroid and its dysfunction affects thyroid hormonogenesis in humans and causes congenital goitrous hypothyroidism.

          Abstract

          Jun Ishii and Atsushi Suzuki et al. report the identification of SLC26A7 as a novel iodide transporter expressed in the thyroid. They identify a nonsense mutation in SLC26A7 in siblings with congenital hypothyroidism and goitre using whole-exome sequencing, implicating this transporter in disease.

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          Mechanisms of thyroid hormone action.

          Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.
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            Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).

            Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.
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              Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome.

              Following the positional cloning of PDS, the gene mutated in the deafness/goitre disorder Pendred syndrome (PS), numerous studies have focused on defining the role of PDS in deafness and PS as well as elucidating the function of the PDS-encoded protein (pendrin). To facilitate these efforts and to provide a system for more detailed study of the inner-ear defects that occur in the absence of pendrin, we have generated a Pds-knockout mouse. Pds(-/-) mice are completely deaf and also display signs of vestibular dysfunction. The inner ears of these mice appear to develop normally until embryonic day 15, after which time severe endolymphatic dilatation occurs, reminiscent of that seen radiologically in deaf individuals with PDS mutations. Additionally, in the second postnatal week, severe degeneration of sensory cells and malformation of otoconia and otoconial membranes occur, as revealed by scanning electron and fluorescence confocal microscopy. The ultrastructural defects seen in the Pds(-/-) mice provide important clues about the mechanisms responsible for the inner-ear pathology associated with PDS mutations.
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                Author and article information

                Contributors
                hamizuno@iuhw.ac.jp
                hkamma@ks.kyorin-u.ac.jp
                Journal
                Commun Biol
                Commun Biol
                Communications Biology
                Nature Publishing Group UK (London )
                2399-3642
                24 July 2019
                24 July 2019
                2019
                : 2
                : 270
                Affiliations
                [1 ]ISNI 0000 0000 9340 2869, GRID grid.411205.3, Department of Pathology, , Kyorin University School of Medicine, ; Tokyo, Japan
                [2 ]ISNI 0000 0001 0702 8004, GRID grid.255137.7, Department of Pathology, , Dokkyo Medical University, ; Tochigi, Japan
                [3 ]ISNI 0000 0001 0728 1069, GRID grid.260433.0, Department of Pediatrics and Neonatology, , Nagoya City University Graduate School of Medical Sciences, ; Nagoya, Japan
                [4 ]ISNI 0000 0000 9340 2869, GRID grid.411205.3, Department of Pharmacology and Toxicology, , Kyorin University School of Medicine, ; Tokyo, Japan
                [5 ]ISNI 0000 0001 2272 1771, GRID grid.467811.d, Division of Biophysics and Neurobiology, Department of Molecular and Cellular Physiology, , National Institute for Physiological Sciences, ; Okazaki, Japan
                [6 ]ISNI 0000 0004 0531 3030, GRID grid.411731.1, Department of Pediatrics, , International University of Health and Welfare, School of Medicine, ; Narita, Japan
                Author information
                http://orcid.org/0000-0001-9623-5442
                http://orcid.org/0000-0001-6911-3351
                Article
                503
                10.1038/s42003-019-0503-6
                6656751
                31372509
                3b317f32-48fd-45b4-99fc-20ffb2136acd
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 July 2018
                : 13 June 2019
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                Custom metadata
                © The Author(s) 2018

                cell biology,genetics,endocrinology,pathogenesis
                cell biology, genetics, endocrinology, pathogenesis

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