TRH Action Is Impaired in Pituitaries of Male IGSF1-Deficient Mice.
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.
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Marc-Olivier
MO
Turgeon
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.|Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
Tanya L
TL
Silander
Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.|Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.
Denica
D
Doycheva
Department of Medicine, The University of Chicago, Chicago, IL , USA.
Xiao-Hui
XH
Liao
Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
Marc
M
Rigden
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Luisina
L
Ongaro
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Xiang
X
Zhou
Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Sjoerd D
SD
Joustra
Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Jan M
JM
Wit
Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
Mike G
MG
Wade
Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
Heike
H
Heuer
Department of Medicine, The University of Chicago, Chicago, IL , USA.|Department of Pediatrics and Committee on Genetics, University of Chicago, Chicago, Illinois .
Samuel
S
Refetoff
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.
Daniel J
DJ
Bernard
D000818:Animals; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000378:metabolism*; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*
D007136:Immunoglobulins; D008565:Membrane Proteins; D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin