Loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1) cause a novel,X-linked syndrome of central hypothyroidism and testicular enlargement |
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| Authors: | N Schoenmakers Y Sun B Bak ASP van Trotsenburg W Oostdijk P Voshol E Cambridge JK White P le Tissier SNM Gharavy JP Martinez-Barbera WH Stokvis-Brantsma T Vulsma MJ Kempers L Persani I Campi M Bonomi P Beck-Peccoz K Chatterjee |
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| Affiliation: | 1. Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK;2. Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands;3. Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands;4. Department of Endocrinology and Metabolic Disorders, Leiden University Medical Center, Leiden, Netherlands;5. Leiden Genome Technology Center, Leiden University Medical Center, Leiden, Netherlands;6. Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada;7. Department of Pediatric Endocrinology, Emma Children''s Hospital, Academic Medical Center, Amsterdam, Netherlands;8. The Sanger Institute Mouse Genetics Project, Wellcome Trust Sanger Institute, Hinxton, UK;9. Neural Development Unit, UCL Institute of Child Health, London, UK;10. Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK;11. Division of Molecular Neuroendocrinology, National Institute for Medical Research, Mill Hill, UK;12. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands;13. Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy;14. Division of Endocrine and Metabolic Disorders, IRCCS Istituto Auxologico Italiano, Milan, Italy;15. Endocrine Unit, Fondazione IRCCS Ca''Granda, Milan, Italy;p. School of Medicine and Pharmacology, Fremantle Hospital Unit, The University of Western Australia, Crawley, Australia;q. Department of Pediatrics, Subdivision of Endocrinology, Erasmus MC-Sophia Children''s Hospital, Rotterdam, Netherlands;r. Department of Paediatrics, West Middlesex University Hospital, Isleworth, UK;s. Hazard Identification Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada |
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| Abstract: | BackgroundCongenital central hypothyroidism occurs either as isolated thyroid-stimulating hormone (TSH) deficiency or in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Hitherto, mutations in the thyrotropin-releasing hormone receptor gene (TRHR) or the TSHb subunit gene (TSHB) are the only known causes of isolated TSH deficiency.MethodsUsing whole exome and candidate gene sequencing, we have studied 11 unrelated families with males exhibiting isolated TSH deficiency, testicular enlargement, and variably low serum prolactin levels.FindingsWe have identified eight distinct mutations and two whole gene deletions disrupting the X-linked immunoglobulin superfamily member 1 gene (IGSF1) in affected males. IGSF1 encodes a pituitary-enriched plasma membrane glycoprotein; disease-associated mutations block trafficking of IGSF1 from the endoplasmic reticulum to the membrane, consistent with loss-of-protein function. Adult male IGSF1 null mice exhibit central hypothyroidism with decreased pituitary TSH content and circulating T3 levels; TSH secretion in response to TRH is blunted and pituitary TRHR mRNA levels are decreased, suggesting that impaired TRH signalling may provide the basis for hypothyroidism.InterpretationOur observations delineate a novel X-linked syndrome in which loss-of-function mutations in IGSF1 cause central hypothyroidism, testicular enlargement, and variable prolactin deficiency, and identify a previously unsuspected role for IGSF1 in hypothalamic-pituitary control of thyroid and testicular function. Variable biochemical penetrance in these families highlights the importance of genetic ascertainment in this syndrome, so that asymptomatic affected individuals can benefit from early initiation of thyroxine treatment.FundingWellcome Trust and National Institute for Health Research Biomedical Research Centre. |
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