Thyroid hormone receptor-beta mutants associated with generalized resistance to thyroid hormone show defects in their ligand-sensitive repression function

Molecular Endocrinology
F J PiedrafitaM Pfahl

Abstract

Thyroid hormone (T3) responses are mediated by two receptors, TR alpha and TR beta, that have been shown to require heterodimer formation with the retinoid-X receptors for effective interaction with most T3-responsive elements (TRE). In addition, it has been shown recently that one type of TRE, an inverted palindrome (IP) with a 4-, 5-, or 6-base pair spacer, can also bind TR homodimers with high affinity. This binding, however, is sensitive to T3, which suggests that TR homodimers could have important biological roles as T3-sensitive repressors. Here we have analyzed eight natural TR beta mutants associated with the syndrome of generalized resistance to thyroid hormone (GRTH). These receptor mutants are characterized by a variably decreased affinity for T3. We show here that their homodimer binding characteristics are altered. For example, kindred GH binds as a homodimer more weakly to DNA than wild-type (WT), whereas mutant PV forms clearly stronger homodimer complexes than WT even in the presence of TREs that bind WT receptor homodimers poorly. Although other mutants were able to bind IP-6 elements efficiently as homodimers, these homodimers showed a decreased sensitivity to T3 in accordance with their reduced affinities for...Continue Reading

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.