Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain.

Parrilla, Roberto L.; Mixson, A. James; McPherson, J A; McClaskey, J H; Weintraub, Bruce D.

doi:10.1172/jci115542

Cited by 245 publications

(172 citation statements)

References 55 publications

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“…A mutation, known as PV (Parrilla et al, 1991), was targeted to the TRα1 gene locus (TRα1PV mice). This mutant results in a complete loss of T3-binding activity and transcriptional capacity.…”

Section: Regulation Of Lipid Homeostasis and Adipogenesis In White Admentioning

confidence: 99%

Thyroid hormone action in metabolic regulation

2011

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Thyroid hormone plays pivotal roles in growth, differentiation, development and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms, diverse thyroid hormone response elements, different heterodimeric partners, coregulators, and the cellular location of TRs. In the present review, we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research, thyroid hormone mimetics application, TR isoform-specific knock-in mouse models, and mitochondrion study with highlights in metabolic regulations. Finally, as future perspectives, we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism.

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Section: Regulation Of Lipid Homeostasis and Adipogenesis In White Admentioning

confidence: 99%

Thyroid hormone action in metabolic regulation

2011

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“…Direct sequencing of the amplified TR β gene was performed by the standard cycle on an automated sequencer, as described elsewhere [6,7]. All members gave their informed consent to participate in this study, and the investigation was performed in accordance with the principles of the Declaration of Helsinki.…”

Section: Case Reportmentioning

confidence: 99%

A Family Showing Resistance to Thyroid Hormone Associated with Chronic Thyroiditis and its Clinical Features: A Case Report

Sato

Sakai

2006

Endocr J

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Abstract. Resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormone, due mainly to mutation of the thyroid hormone receptor (TR) β gene. It has been reported that serum of patients with RTH lacks autoantibodies against thyroglobulin (Tg) and thyroid peroxidase (TPO), except in rare cases where there is cooccurrence of coincidental autoimmune thyroiditis. Here we describe the five-year medical history of a Japanese woman and her father with RTH and coincidental chronic thyroiditis. The woman, aged 28 years, was referred to our hospital because of suspected hyperthyroidism. She showed a normal level of TSH and elevated levels of free triiodothyronine (FT3) and free thyroxine (FT4). Anti-Tg and anti-TPO antibodies were slightly positive. Since RTH was suspected, her parents were investigated with informed consent. Her father showed elevated levels of TSH, FT3 and FT4, and was positive for both anti-Tg antibody and anti-TPO antibody. Her mother had hypothyroidism caused by chronic thyroiditis. Sequencing of the TR β gene showed that the patient and her father had a codon 453 mutation resulting in a CCT (proline) to ACT (threonine) substitution. The patient gradually developed emotional disturbance, and was admitted to a psychiatry ward for two months, where she was treated with lorazepam and her condition improved. Her father, on the other hand, has been doing well for five years. The patient and the father showed different clinical courses, even though they carried the same mutation of the TR β gene. The fact that the father showed an elevated TSH level, whereas the patient did not, was thought to be due to decreased thyroid function caused by chronic thyroiditis.

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“…This mutant mouse was created by a targeted mutation of thyroid hormone b receptor (TRbPV) via homologous recombination and the CreLoxP system (Kaneshige et al, 2000). The thyroid hormone receptor b mutant (denoted as PV) was identified in a patient (PV) with resistance to thyroid hormone (RTH) (Parrilla et al, 1991). RTH is caused by mutations of the TRb gene and manifests symptoms as a result of decreased sensitivity to the thyroid hormone (T3) in target tissues (Yen, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…RTH is caused by mutations of the TRb gene and manifests symptoms as a result of decreased sensitivity to the thyroid hormone (T3) in target tissues (Yen, 2003). PV has a C-insertion at codon 448 that produces a frame shift in the carboxylterminal 14 amino acids of TRb1 (Parrilla et al, 1991). PV has completely lost thyroid hormone (T3) binding and exhibits potent dominant-negative activity (Meier et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

et al. 2005

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The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor b (TRb PV/PV mouse) spontaneously develop follicular thyroid carcinoma similar to human thyroid cancer. Using this mutant mouse, we tested the hypothesis that the peroxisome proliferator-activated receptor c (PPARc) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TRb PV/ þ and PPARc þ /À mice, we found that thyroid carcinogenesis progressed significantly faster in TRb PV/PV mice with PPARc insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPARc protein abundance led to the activation of the nuclear factor-jB signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TRb PV/PV mice with a PPARc agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPARc is a critical modifier in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.

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Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain.

Abstract: Genetic analysis in our laboratory of families with generalized thyroid hormone resistance (GTHR) has demonstrated tight linkage with a locus, c-erbAft, encoding a nuclear T3 receptor.

Cited by 245 publications

References 55 publications

Thyroid hormone action in metabolic regulation

Thyroid hormone action in metabolic regulation

A Family Showing Resistance to Thyroid Hormone Associated with Chronic Thyroiditis and its Clinical Features: A Case Report

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

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