University of Oulu

Cangul, H., Liao, X., Schoenmakers, E., Kero, J., Barone, S., Srichomkwun, P., Iwayama, H., Serra, E., Saglam, H., Eren, E., Tarim, O., Nicholas, A., Zvetkova, I., Anderson, C., Frankl, F., Boelaert, K., Ojaniemi, M., Jääskeläinen, J., Patyra, K., Löf, C., Williams, E., Soleimani, M., Barrett, T., Maher, E., Chatterjee, V., Refetoff, S., Schoenmakers, N. (2018) Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism. JCI insight, 3 (20), e99631. doi:10.1172/jci.insight.99631

Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

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Author: Cangul, Hakan1; Liao, Xiao-Hui2; Schoenmakers, Erik3;
Organizations: 1Department of Medical Genetics, Istanbul Medipol University, International School of Medicine
2Department of Medicine, The University of Chicago
3Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge
4Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku
5Department of Paediatrics, Turku University Hospital
6University of Cincinnati and Veterans Administration Hospital
7Department of Human Genetics, The Wellcome Trust Sanger Institute
8Uludag University School of Medicine, Department of Paediatric Endocrinology
9Department of Medical Genetics and Division of Renal Medicine, University of Cambridge
10Institute of Metabolism and Systems Research, University of Birmingham and Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners
11PEDEGO Research Center and MRC Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital
12Department of Pediatrics, University of Eastern Finland and Kuopio University Hospital
13Thyroid Carcinogenesis Group, University of Cambridge, Strangeways Research Laboratory
14The UK10K Consortium detailed in the Supplemental Acknowledgments
15Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham and Department of Endocrinology, Birmingham Children’s Hospital
16Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre
17Department of Pediatrics and the Committee on Genetics, The University of Chicago
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.4 MB)
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Language: English
Published: American Society for Clinical Investigation, 2018
Publish Date: 2018-12-10


Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation.SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

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Series: JCI insight
ISSN: 2379-3708
ISSN-E: 2379-3708
ISSN-L: 2379-3708
Volume: 3
Issue: 20
Article number: e99631
DOI: 10.1172/jci.insight.99631
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study made use of data generated by the UK10K Project with funding from the Wellcome Trust, UK (WT091310) and we acknowledge the contribution of the UK10K Consortium. A full list of the UK10K investigators who contributed to the generation of the data is available from This work was also supported by Wellcome Trust grants 100585/Z/12/Z (to NS) and 095564/Z/11/Z (to VKC), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Center (to VKC and NS). EGS and CAA are supported by the Wellcome Trust (098051) and EM holds an NIHR Senior Investigator Award. The University of Cambridge has received salary support with respect to EM from the NHS in the East of England through the Clinical Academic Reserve. Most studies carried out in Slc26a7-null mice were supported by a grant from the NIH (R37DK15070 to SR), as were XHL, PS, and HI. HC was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) with grant no. 116S389. We acknowledge the Genomics/Transcriptomics, Imaging, Histology and Disease Model Core Facilities in the Wellcome Trust-MRC Institute of Metabolic Science. The Histology Facility is supported by the UK Medical Research Council (MRC) Metabolic Disease Unit grant (MRC_MC_UU_12012/5) and the Imaging Facility by a Wellcome Trust Strategic Award (100574/Z/12/Z); the Genomics/Transcriptomics and Disease Model Core Facilities are supported by both of these awards. Families A and B were investigated in the NIHR Wellcome Clinical Research Facility, Birmingham, and we acknowledge their expert support. We also acknowledge Lorraine Everett for her contribution to generating the FLAG-Slc26a7 mouse model at the Wellcome Trust Sanger Institute, which was supported by the Wellcome Trust (grant 098051), and Fiona Gribble and Frank Reimann at the Wellcome Trust-MRC Institute of Metabolic Science for expert advice. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NHS, the Department of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, or the NIH.
Dataset Reference: Supplemental data:
Copyright information: Copyright © 2018 American Society for Clinical Investigation. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit