TSHR gene

TSHR (Thyroid Stimulating Hormone Receptor) is a protein-coding gene located on chromosome 14q24-q31. Three transcript variants encoding different isoforms have been found for this gene. An important paralog of this gene is LHCGR.

The receptor protein encoded by this gene(TSH-R) is a membrane protein and an important regulator of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin. Its activity is mediated by adenylate cyclase. Defects in this gene are a cause of various types of hyperthyroidism.

Diseases associated with TSHR include congenital hypothyroidism.

Significance of TSH receptor in extrathyroidal diseases: Graves' orbitopathy (GO) is present in ~26% of cases at presentation of GD or occurs less frequently during the course. It is an autoimmunity-related phenomenon causing orbital lymphocytic infiltration with a predominance of T lymphocytes, edema and an increase in orbital connective tissue, adipose tissue and extraocular muscle volume. The TSH-R is currently considered the main autoantigen in ophthalmopathy and the periorbital fibroblasts as the target of the autoimmune attack. In patients with recent GO, TSHRAbs levels directly correlate with orbital disease activity and may predict clinical outcome. Stimulation of TSH-R in orbital fibroblasts by TSHRAbs leads to activation of intracellular signaling pathways, production of glycosaminoglycans, and an increase in proliferation, adipogenesis, and myofibrillogenesis. Increased TSH-R expression has been shown to be influenced by autoimmune and inflammatory processes and is associated with de novo adipogenesis.

TSH-R has also been implicated in Graves' dermatopathy. Similar to GO, this rare manifestation is associated with high titers of TSHRAbs and is characterized by a large amount of glycosaminoglycans distributed in the reticular part of the dermis. TSH-R immunoreactivity has been detected in the prepuce of patients with Graves' dermatopathy.

The thyroid-stimulating hormone receptor (TSH-R) is predominantly expressed in the basolateral membrane of thyrocytes, where it stimulates almost every aspect of their metabolism. Several extrathyroidal localizations of the receptor have been found, including the pituitary gland, hypothalamus and other areas of the central nervous system, periorbital tissue, skin, kidney, adrenal gland, liver, immune system cells, blood cells and vascular tissue, adipose tissue, cardiac and skeletal muscle, and bone. Although the functionality of the receptor has been demonstrated in most of these tissues, its physiological significance is still controversial. In some cases, a contribution to several pathological processes is evident, such as in Grave's disease with its multiple manifestations. In

In the context of other thyroid abnormalities, however, the contribution of TSH-R and its ligand is still controversial. This article provides an overview of the different sites where TSH-R is expressed and its potential role in physiological and pathological processes.

1. Costagliola S et al. (2002) Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors. EMBO J 21:504-513.
2. Nakabayashi K et al. (2002) Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. J Clin Invest 109:1445-1452.