TY - JOUR
T1 - Thyroid Hormone Hyposensitivity
T2 - From Genotype to Phenotype and Back
AU - Rurale, Giuditta
AU - Cicco, Emery Di
AU - Dentice, Monica
AU - Salvatore, Domenico
AU - Persani, Luca
AU - Marelli, Federica
AU - Luongo, Cristina
N1 - Funding Information:
Funding. This work was partially supported by the grant 05C102_2011 of the Ricerca Corrente of the Istituto Auxologico Italiano (Milan, Italy).
Publisher Copyright:
© Copyright © 2020 Rurale, Cicco, Dentice, Salvatore, Persani, Marelli and Luongo.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1/24
Y1 - 2020/1/24
N2 - Thyroid hormone action defects (THADs) have been classically considered conditions of impaired sensitivity to thyroid hormone (TH). They were originally referring to alterations in TH receptor genes (THRA and THRB), but the discovery of genetic mutations and polymorphisms causing alterations in cell membrane transport (e.g., MCT8) and metabolism (e.g., SECISBP2, DIO2) led recently to a new and broader definition of TH hyposensitivity (THH), including not only THADs but all defects that could interfere with the activity of TH. Due to the different functions and tissue-specific expression of these genes, affected patients exhibit highly variable phenotypes. Some of them are characterized by a tissue hypothyroidism or well-recognizable alterations in the thyroid function tests (TFTs), whereas others display a combination of hypo- and hyperthyroid manifestations with normal or only subtle biochemical defects. The huge effort of basic research has greatly aided the comprehension of the molecular mechanisms underlying THADs, dissecting the morphological and functional alterations on target tissues, and defining the related-changes in the biochemical profile. In this review, we describe different pictures in which a specific alteration in the TFTs (TSH, T4, and T3 levels) is caused by defects in a specific gene. Altogether these findings can help clinicians to early recognize and diagnose THH and to perform a more precise genetic screening and therapeutic intervention. On the other hand, the identification of new genetic variants will allow the generation of cell-based and animal models to give novel insight into thyroid physiology and establish new therapeutic interventions.
AB - Thyroid hormone action defects (THADs) have been classically considered conditions of impaired sensitivity to thyroid hormone (TH). They were originally referring to alterations in TH receptor genes (THRA and THRB), but the discovery of genetic mutations and polymorphisms causing alterations in cell membrane transport (e.g., MCT8) and metabolism (e.g., SECISBP2, DIO2) led recently to a new and broader definition of TH hyposensitivity (THH), including not only THADs but all defects that could interfere with the activity of TH. Due to the different functions and tissue-specific expression of these genes, affected patients exhibit highly variable phenotypes. Some of them are characterized by a tissue hypothyroidism or well-recognizable alterations in the thyroid function tests (TFTs), whereas others display a combination of hypo- and hyperthyroid manifestations with normal or only subtle biochemical defects. The huge effort of basic research has greatly aided the comprehension of the molecular mechanisms underlying THADs, dissecting the morphological and functional alterations on target tissues, and defining the related-changes in the biochemical profile. In this review, we describe different pictures in which a specific alteration in the TFTs (TSH, T4, and T3 levels) is caused by defects in a specific gene. Altogether these findings can help clinicians to early recognize and diagnose THH and to perform a more precise genetic screening and therapeutic intervention. On the other hand, the identification of new genetic variants will allow the generation of cell-based and animal models to give novel insight into thyroid physiology and establish new therapeutic interventions.
KW - thyroid hormone cell membrane transport defects
KW - thyroid hormone hyposensitivity
KW - thyroid hormone metabolism defects
KW - thyroid hormones
KW - thyroid hormones action defects
UR - http://www.scopus.com/inward/record.url?scp=85079170040&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079170040&partnerID=8YFLogxK
U2 - 10.3389/fendo.2019.00912
DO - 10.3389/fendo.2019.00912
M3 - Review article
AN - SCOPUS:85079170040
VL - 10
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
SN - 1664-2392
M1 - 912
ER -