Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

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The authors thank X.-H. Liao from the Refetoff laboratory (The University of Chicago, supported by US National Institutes of Health (NIH) grant DK15700) for measuring T4, T3, FT4I and TSH in mice, P. Scheiffele for the antibody to IGSF1 CTD and S. Kimmins (McGill University) and P. Bisschop (Academic Medical Center, University of Amsterdam) for human testis and pituitary RNA, respectively. We also thank H. Bikker, J.C. Moreno, A. Escudero, E. Aten, M. Losekoot, E. Endert, J.W.A. Smit, R.van Rijn and E.L. van Persijn-van Meerten for technical support and advice. We thank F.J. de Jong and Y. de Rijke for measuring serum inhibin B and AMH and for providing age references. We thank S. Tran and X. Zhou for assistance with collection of mouse serum samples. We acknowledge the help of N. Zwaveling, J. Gosen, E.J. Schroor, L.C.G. de Graaff and G. Radetti in providing clinical data. We acknowledge The Eastern Region Sequencing and Informatics Hub (see URLs), who undertook sequencing and preliminary bioinformatics analyses of data from the UK families. We thank the subjects and their families for participating. Our work was supported in part by a grant from the China Scholarship Council (to Y.S.); a National Sciences and Engineering Research Council (NSERC) Doctoral Research Award (to B.B.), NSERC Discovery Grant 341801-07 and a Fonds de la Recherche en Santé du Québec (FRSQ) Chercheur Boursier Senior Award (to D.J.B.); grants from the Wellcome Trust (095564 to N.S. and K.C.; WT077157/Z/05/Z to E.C. and J.K.W.; 084361, 078432 and 086545 to J.P.M.-B.), the National Institutes of Health Research Cambridge Biomedical Research Centre (to N.S. and K.C.) and the UK Medical Research Council (MRC; U117570590 to P.l.T.); a National Health and Medical Research Council of Australia Practitioner Fellowship (to T.M.E.D.); the Dutch Growth Research Foundation (D.G.D.B.); the Young Investigator grant of the Italian Ministry of Health and Istituto Auxologico Italiano IRCCS (GR-2008-1137632 to M.B.); and the Great Ormond Street Children's Hospital Charity (to M.T.D.).

Author information

Author notes

    • Yu Sun
    • , Beata Bak
    • , Nadia Schoenmakers
    •  & A S Paul van Trotsenburg

    These authors contributed equally to this work.

    • Krishna Chatterjee
    • , Mehul T Dattani
    • , Jan M Wit
    •  & Daniel J Bernard

    These authors jointly directed this work.


  1. Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

    • Yu Sun
    • , Claudia A L Ruivenkamp
    • , Jeroen F J Laros
    • , Marjolein Kriek
    • , Sarina G Kant
    • , Cathy A J Bosch
    • , Johan T den Dunnen
    •  & Martijn H Breuning
  2. Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.

    • Beata Bak
    •  & Daniel J Bernard
  3. Institute of Metabolic Science, Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

    • Nadia Schoenmakers
    • , Peter Voshol
    •  & Krishna Chatterjee
  4. Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • A S Paul van Trotsenburg
    • , Thomas Vulsma
    • , Marlies J Kempers
    •  & Raoul C Hennekam
  5. Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

    • Wilma Oostdijk
    • , Wilhelmina H Stokvis-Brantsma
    •  & Jan M Wit
  6. The Sanger Institute Mouse Genetics Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Emma Cambridge
    •  & Jacqueline K White
  7. Neural Development Unit, University College London (UCL) Institute of Child Health, London, UK.

    • Paul le Tissier
    • , S Neda Mousavy Gharavy
    •  & Juan P Martinez-Barbera
  8. Division of Molecular Neuroendocrinology, National Institute for Medical Research, Mill Hill, London, UK.

    • Paul le Tissier
  9. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

    • Marlies J Kempers
  10. Department of Clinical Sciences & Community Health, Università degli Studi di Milano, Milan, Italy.

    • Luca Persani
    • , Irene Campi
    •  & Paolo Beck-Peccoz
  11. Division of Endocrine and Metabolic Disorders, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Auxologico Italiano, Milan, Italy.

    • Luca Persani
    •  & Marco Bonomi
  12. Endocrine Unit, Fondazione IRCCS Ca'Granda, Milan, Italy.

    • Irene Campi
    •  & Paolo Beck-Peccoz
  13. School of Medicine and Pharmacology, Fremantle Hospital Unit, The University of Western Australia, Perth, Western Australia, Australia.

    • Hongdong Zhu
    •  & Timothy M E Davis
  14. Subdivision of Endocrinology, Department of Pediatrics, Erasmus Medical Center–Sophia Children's Hospital, Rotterdam, The Netherlands.

    • Anita C S Hokken-Koelega
    •  & Daria Gorbenko Del Blanco
  15. Department of Paediatrics, West Middlesex University Hospital, Isleworth, UK.

    • Jayanti J Rangasami
  16. Department of Endocrinology and Metabolic Disorders, Leiden University Medical Center, Leiden, The Netherlands.

    • Nienke R Biermasz
    • , Natasha M Appelman-Dijkstra
    • , Eleonora P Corssmit
    • , Guido C J Hovens
    •  & Alberto M Pereira
  17. Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.

    • Johan T den Dunnen
  18. Hazard Identification Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.

    • Michael G Wade
  19. Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK.

    • Mehul T Dattani


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Y.S., J.T.d.D., M.K., N.S. and K.C. developed the exome sequencing protocol. A.S.P.v.T., W.O., S.G.K., N.R.B., N.M.A.-D., A.M.P., M.H.B., R.C.H., M.T.D., N.S., L.P., I.C., M.B., P.B.-P., H.Z., T.M.E.D., K.C., A.C.S.H.-K., D.G.D.B. and J.M.W. designed the clinical research studies. Y.S., J.F.J.L. and N.S. performed bioinformatics analyses, mutational analysis and genotyping. B.B. generated the vectors expressing mutant IGSF1 and performed all associated biochemical analyses; maintained the mouse colony, collected all mouse tissues and plasma, and analyzed pituitary gene expression; and prepared figures. D.J.B. generated the mouse model, supervised all in vitro and mouse work and participated in data collection and construction of the figures. P.V. and M.G.W. contributed to mouse phenotyping. E.C., J.K.W. and M.G.W. performed mouse T4 measurements. P.l.T. performed measurements of pituitary TSH and prolactin content. S.N.M.G. and J.P.M.-B. carried out the IGSF1 expression studies in mouse and human embryos. C.A.L.R. and C.A.J.B. performed and analyzed the microarray and hybridization experiments. A.S.P.v.T., W.O., W.H.S.-B., T.V., M.J.K., L.P., I.C., M.B., P.B.-P., H.Z., T.M.E.D., A.C.S.H.-K., D.G.D.B., J.J.R., S.G.K., N.R.B., N.M.A.-D., A.M.P., G.C.J.H., E.P.C., M.H.B., R.C.H., A.C.S.H.-K. and M.T.D. contributed to clinical evaluations and the delineation of the subject phenotypes. Y.S., B.B., N.S., A.S.P.v.T., K.C., M.T.D., R.C.H., D.J.B. and J.M.W. prepared the manuscript. D.J.B., J.M.W., K.C. and M.T.D. conceived and supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Krishna Chatterjee or Mehul T Dattani or Jan M Wit or Daniel J Bernard.

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