Human Genome and Diseases: Review¶The TSH receptor and its role in thyroid disease

Abstract

The thyrotropin (TSH) receptor plays a preeminent role in thyroid physiology and disease. TSH, acting through the TSH receptor, is the major stimulator of thyroid cell growth, differentiation and function. In Graves' disease, the TSH receptor is the target of stimulating antibodies that cause hyperthyroidism. Although still a topic of debate, the TSH receptor has been implicated in the pathogenesis of the endocrine ophthalmopathy associated with Graves' disease. Blocking antibodies against the TSH receptor are involved in the development of hypothyroidism in a subset of patients with autoimmune hypothyroidism. Transplacental passage of stimulating or blocking TSH receptor antibodies from a mother with autoimmune thyroid disease may result in transient hyper- or hypothyroidism in early infancy. During pregnancy, the placental hormone human choriogonadotropin (hCG) can cause gestational hyperthyroidism through cross-reaction with the TSH receptor. Gestational hyperthyroidism may also be involved in the pathogenesis of hyperemesis gravidarum. Trophoblast tumors secreting hCG are a rare cause of hyperthyroidism. Somatic activating mutations of the TSH receptor have been identified as a molecular cause of toxic adenomas, whereas activating mutations in the germline give rise to nonautoimmune familial hyperthyroidism or sporadic congenital hyperthyroidism. These gain-of-function mutations are dominant, and one mutated allele is sufficient to result in disease. Inactivating germline mutations of both TSH receptor alleles lead to variable degrees of resistance to TSH, encompassing a spectrum ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with thyroid hypoplasia.

Potential Utility and Limitations of Thyroid Cancer Cell Lines as Models for Studying Thyroid Cancer

“…These markers also help in evaluating the differentiation status of thyroid cancers and cell lines (16)(17)(18)(19) (Fig. 1 and Table 3).…”

CTLA-4 and its role in autoimmune thyroid disease

“…Increased circulating activated T cells and thyroid-specific autoantibodies occur in Graves' disease. Antibodies directed against the TSH receptor stimulate thyroid function and lead to glandular overactivity (Kopp 2001). Depending on its severity, Graves' disease is classified as subclinical or overt hyperthyroidism.…”

Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism

“…However, numerous studies have identified genetic lesions within key components of the TSH receptor (TSHR) signalling pathway in human TNG (Tonacchera et al 2000, Yen et al 2000, Corvilain et al 2001, Kopp 2001. Most mutations have been identified in the TSHR gene, with up to 82% of cases of human TNG having identifiable TSHR mutations (Parma et al 1997).…”

“…Most mutations have been identified in the TSHR gene, with up to 82% of cases of human TNG having identifiable TSHR mutations (Parma et al 1997). These mutations are generally within exon 10 of the TSHR gene, specifically within the transmembrane domain, and a 'hot spot' for gain-of-function mutations has been identified at amino acids 619-650 (Yen et al 2000, Kopp 2001.…”