Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

Yu Sun, Beata Bak, Nadia Schoenmakers, A. S Paul Van Trotsenburg, Wilma Oostdijk, Peter Voshol, Emma Cambridge, Jacqueline K. White, Paul Le Tissier, S. Neda Mousavy Gharavy, Juan P. Martinez-Barbera, Wilhelmina H. Stokvis-Brantsma, Thomas Vulsma, Marlies J. Kempers, Luca Persani, Irene Campi, Marco Bonomi, Paolo Beck-Peccoz, Hongdong Zhu, Timothy M E DavisAnita C S Hokken-Koelega, Daria Gorbenko Del Blanco, Jayanti J. Rangasami, Claudia A L Ruivenkamp, Jeroen F J Laros, Marjolein Kriek, Sarina G. Kant, Cathy A J Bosch, Nienke R. Biermasz, Natasha M. Appelman-Dijkstra, Eleonora P. Corssmit, Guido C J Hovens, Alberto M. Pereira, Johan T D Den Dunnen, Michael G. Wade, Martijn H. Breuning, Raoul C. Hennekam, Krishna Chatterjee, Mehul T. Dattani, Jan M. Wit, Daniel J. Bernard

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1375-1381
Number of pages7
JournalNature Genetics
Issue number12
Publication statusPublished - Dec 2012

ASJC Scopus subject areas

  • Genetics


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