BSPED2012 Oral Communications Oral Communications 1 (8 abstracts)
Loss-of-function mutations in IGSF1 cause a novel, X-linked syndrome of central hypothyroidism and testicular enlargement
Nadia Schoenmakers 1 , Beata Bak 2 , Yu Sun 3 , Paul van Trotsenburg 4 , Wilma Oostdijk 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 3 , Martijn Breuning 3 , Raoul Hennekam 4 , V Krishna Chatterjee 1 , Mehul Dattani 11 , Daniel Bernard 2 & Jan-Maarten Wit 3
1Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; 3Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands; 4Department of Paediatric Endocrinology, Academic Medical Centre, Emma Children’s Hospital, Amsterdam, The Netherlands; 5Department of Pediatrics, Leiden University Medical Centre, Leiden, The Netherlands; 6Department of Medical Sciences, Universita Degli Studi di Milano, Milan, Italy; 7School of Medicine and Pharmacology, Freemantle Hospital Unit, 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 ten unrelated families with males exhibiting isolated TSH deficiency, testicular enlargement and variably low serum prolactin levels.
Results: We have identified nine distinct mutations 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 T4 levels, together with increased body weight and fat mass, recapitulating features of the human disorder. Decreased TRHR mRNA levels in pituitaries from null mice, together with reduced TSH bioactivity in patients with IGSF1 mutations, suggest 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.
Volume 30
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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