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

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


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.

MeSH terms

  • Animals
  • Immunoglobulins / genetics*
  • Immunoglobulins / metabolism
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Pituitary Gland / metabolism*
  • Receptors, Thyrotropin-Releasing Hormone / genetics
  • Receptors, Thyrotropin-Releasing Hormone / metabolism*
  • Signal Transduction / physiology
  • Thyrotropin / genetics
  • Thyrotropin / metabolism*
  • Thyrotropin-Releasing Hormone / genetics
  • Thyrotropin-Releasing Hormone / metabolism*


  • Immunoglobulins
  • Membrane Proteins
  • Receptors, Thyrotropin-Releasing Hormone
  • Thyrotropin-Releasing Hormone
  • Thyrotropin