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Endocrinology. 2017 Apr 1;158(4):815-830. doi: 10.1210/en.2016-1788.

TRH Action Is Impaired in Pituitaries of Male IGSF1-Deficient Mice.

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Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.
Department of Medicine, The University of Chicago, Chicago, IL , USA.
Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Department of Pediatrics and Committee on Genetics, University of Chicago, Chicago, Illinois .


Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene cause central hypothyroidism. IGSF1 is a transmembrane glycoprotein of unknown function expressed in thyrotropin (TSH)-producing thyrotrope cells of the anterior pituitary gland. The protein is cotranslationally cleaved, with only its C-terminal domain (CTD) being trafficked to the plasma membrane. Most intragenic IGSF1 mutations in humans map to the CTD. In this study, we used CRISPR-Cas9 to introduce a loss-of-function mutation into the IGSF1-CTD in mice. The modified allele encodes a truncated protein that fails to traffic to the plasma membrane. Under standard laboratory conditions, Igsf1-deficient males exhibit normal serum TSH levels as well as normal numbers of TSH-expressing thyrotropes. However, pituitary expression of the TSH subunit genes and TSH protein content are reduced, as is expression of the receptor for thyrotropin-releasing hormone (TRH). When challenged with exogenous TRH, Igsf1-deficient males release TSH, but to a significantly lesser extent than do their wild-type littermates. The mice show similarly attenuated TSH secretion when rendered profoundly hypothyroid with a low iodine diet supplemented with propylthiouracil. Collectively, these results indicate that impairments in pituitary TRH receptor expression and/or downstream signaling underlie central hypothyroidism in IGSF1 deficiency syndrome.

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