Format

Send to

Choose Destination

See 1 citation found by title matching your search:

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.

Author information

1
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
2
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
3
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
4
Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
5
Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.
6
Department of Medicine, The University of Chicago, Chicago, IL , USA.
7
Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
8
Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
9
Department of Pediatrics and Committee on Genetics, University of Chicago, Chicago, Illinois .

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.

PMID:
28324000
PMCID:
PMC5460797
DOI:
10.1210/en.2016-1788
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center