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

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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Turgeon MO,Silander TL,Doycheva D,Liao XH,Rigden M,Ongaro L,Zhou X,Joustra SD,Wit JM,Wade MG,Heuer H,Refetoff S,Bernard DJ

doi

10.1210/en.2016-1788

subject

Has Abstract

pub_date

2017-04-01 00:00:00

pages

815-830

issue

4

eissn

0013-7227

issn

1945-7170

pii

2896908

journal_volume

158

pub_type

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