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Turgeon, Marc-Olivier; Silander, Tanya L; Doycheva, Denica; Liao, Xiao-Hui; Rigden, Marc; Ongaro, Luisina; Zhou, Xiang; Joustra, Sjoerd D; Wit, Jan M; Wade, Mike G; Heuer, Heike; Refetoff, Samuel; Bernard, Daniel J
Endocrinology (Philadelphia), 04/2017, Letnik: 158, Številka: 4Journal Article
Abstract 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. Igsf1-deficient mice have reduced pituitary TRH receptor expression and are, therefore, less sensitive to TRH stimulated TSH synthesis and secretion.
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