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Nature Research, Nature Genetics, 12(44), p. 1375-1381, 2012

DOI: 10.1038/ng.2453

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

Journal article published in 2012 by Yu Sun, Beata Bak, van Trotsenburg As, Nadia Schoenmakers, A. S. Paul van Trotsenburg, As S. Paul van Trotsenburg ORCID, Jtd Den Dunnen, Wilma Oostdijk, Peter Voshol, White Jk, Emma Cambridge, Gharavy Sn, Jacqueline K. White, Paul le Tissier, Paul le Tissier and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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. © 2012 Nature America, Inc. All rights reserved.