TY - JOUR
T1 - Central Tolerance Mechanisms to TSHR in Graves' Disease
T2 - Contributions to Understand the Genetic Association
AU - Pujol-Borrell, Ricardo
AU - Álvarez-Sierra, Daniel
AU - Jaraquemada, Dolores
AU - Marín-Sánchez, Ana
AU - Colobran, Roger
N1 - Funding Information:
Recent work by the authors described in this review was supported by grants PI1400848 and PI1700324 by the Instituto de Salud Carlos III that was co-financed by the European Regional Development Fund (ERDF).
Publisher Copyright:
© 2018 Georg Thieme Verlag KG Stuttgart - New York.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - © 2018 Georg Thieme Verlag KG Stuttgart - New York. In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves' disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.
AB - © 2018 Georg Thieme Verlag KG Stuttgart - New York. In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves' disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.
KW - Graves' disease
KW - TSHR
KW - central tolerance
KW - genetic association
KW - genetics of Graves' disease
UR - http://www.scopus.com/inward/record.url?scp=85058031475&partnerID=8YFLogxK
U2 - 10.1055/a-0755-7927
DO - 10.1055/a-0755-7927
M3 - Article
C2 - 30396220
SN - 0018-5043
VL - 50
SP - 863
EP - 870
JO - Hormone and Metabolic Research
JF - Hormone and Metabolic Research
IS - 12
ER -
