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Thyrotropin receptor–associated diseases: from adenomata to Graves disease
Terry F. Davies, … , Yaron Tomer, Rauf Latif
Terry F. Davies, … , Yaron Tomer, Rauf Latif
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):1972-1983. https://doi.org/10.1172/JCI26031.
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Science in Medicine

Thyrotropin receptor–associated diseases: from adenomata to Graves disease

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Abstract

The thyroid-stimulating hormone receptor (TSHR) is a G protein–linked, 7–transmembrane domain (7-TMD) receptor that undergoes complex posttranslational processing unique to this glycoprotein receptor family. Due to its complex structure, TSHR appears to have unstable molecular integrity and a propensity toward over- or underactivity on the basis of point genetic mutations or antibody-induced structural changes. Hence, both germline and somatic mutations, commonly located in the transmembrane regions, may induce constitutive activation of the receptor, resulting in congenital hyperthyroidism or the development of actively secreting thyroid nodules. Similarly, mutations leading to structural alterations may induce constitutive inactivation and congenital hypothyroidism. The TSHR is also a primary antigen in autoimmune thyroid disease, and some TSHR antibodies may activate the receptor, while others inhibit its activation or have no influence on signal transduction at all, depending on how they influence the integrity of the structure. Clinical assays for such antibodies have improved significantly and are a useful addition to the investigative armamentarium. Furthermore, the relative instability of the receptor can result in shedding of the TSHR ectodomain, providing a source of antigen and activating the autoimmune response. However, it may also provide decoys for TSHR antibodies, thus influencing their biological action and clinical effects. This review discusses the role of the TSHR in the physiological and pathological stimulation of the thyroid.

Authors

Terry F. Davies, Takao Ando, Reigh-Yi Lin, Yaron Tomer, Rauf Latif

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Figure 1

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TSHR structure. This computer model of the TSHR shows the 7 TMDs (spiral...
TSHR structure. This computer model of the TSHR shows the 7 TMDs (spirals) embedded within the plasma membrane and a short cytoplasmic tail, which together make up the β/B subunit. The unique 50-aa–long cleaved region (about 316–366 aa) is shown in gray. Forming a long array, the 9 LRRs, each consisting of 20–24 aa, are depicted as spirals (α helices and β pleated sheets) on the ectodomain of the receptor and make up the major portion of the α/A subunit. The LRRs have a characteristic horseshoe shape with a concave inner surface. C, C-terminus; N, N-terminus. Figure adapted with permission from Thyroid (28).
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