SFEBES2013 Oral Communications Steroids and thyroid (8 abstracts)
Loss-of-function mutations in IGSF1 cause a novel, X-linked syndrome of central hypothyroidism and testicular enlargement
Nadia Schoenmakers 1 , Yu Sun 2 , Beata Bak 3 , Paul van Trotsenburg 4 , Wilma Oostdyk 5 , Peter Voshol 1 , Luca Persani 6 , Timothy Davis 7 , Paul le Tissier 8 , Neda Gharavy 9 , Natasha Appelman-Dijkstra 10 , Alberto Pereira 10 , Johan den Dunnen 2 , Martijn Breuning 2 , Raoul Hennekam 4 , V Krishna Chatterjee 1 , Mehul Dattani 11 , Daniel Bernard 3 & Jan-Maarten Wit 2
1Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands; 3Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; 4Department of Paediatric Endocrinology, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands; 5Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands; 6Department of Clinical Sciences and Community Health, Universita degli Studi di Milano, Milan, Italy; 7Freemantle Hospital Unit, School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia; 8Division of Molecular Neuroendocrinology, National Institute for Medical Research, Mill Hill, UK; 9Neural Development Unit, UCL Institute of Child Health, London, UK; 10Department of Endocrinology and Metabolic Disorders, Leiden University Medical Centre, Leiden, The Netherlands; 11Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.
Introduction: Congenital central hypothyroidism occurs either as isolated 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 TRH receptor (TRHR) or TSHβ subunit (TSHB) genes are the only known causes of isolated TSH deficiency.
Methods: Using 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.
Results: We have identified eight distinct mutations and two whole gene deletions in the X-linked immunoglobulin superfamily member 1 (IGSF1) gene 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. We have also characterised IGSF1-deficient mice. Adult male IGSF1 null mice show decreased pituitary TSH content and circulating T3 levels, and increased body weight, recapitulating features of the human disorder. Elevated hypothalamic TRH levels in null mice, in association with decreased pituitary TRHR mRNA levels and blunted serum TSH responses to TRH testing suggests that impaired TRH signalling may be the basis for hypothyroidism.
Conclusions: Collectively, our 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.
Declaration of funding
This work was supported by the Wellcome Trust (grants 095564, 077157/Z/05/Z, 084361, 078432, 086545), the MRC (U117570590) and Great Ormond Street Childrens Hospital Charity.
Volume 31
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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