Transducin β-like 1, X-linked and nuclear receptor co-repressor cooperatively augment the ligand-independent stimulation of TRH and TSHβ gene promoters by thyroid hormone receptors

Takamizawa, Tetsuya; Satoh, Tetsurou; Miyamoto, T.; Nakajima, Yasuyo; Ishizuka, Takashi; Tomaru, Takuya; Yoshino, Satoshi; Katano-Toki, Akiko; Nishikido, Ayaka; Yamada, Masanobu; Watanabe, Takuya; Okamura, Takashi; Ishida, Emi; Horiguchi, Kazuhiko; Matsumoto, Syunichi; Ishii, Sumiyasu; Ozawa, Atsushi; Shibusawa, Nobuyuki; Okada, Shuichi; Yamada, Masanobu

doi:10.1507/endocrj.ej17-0384

Cited by 7 publications

(6 citation statements)

References 22 publications

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“…Recently, Takamizawa et al . (49) have demonstrated that the ligand-independent thyroid hormone receptor-mediated stimulation of TSHB and TRH promoters was enhanced by TBL1X alone or by cotransfection with TBL1X and NCoR (Fig. 2c); however, the stimulating effect was attenuated by cotransfection with TBL1X mutants (p.Asn365Tyr and p.Tyr458Cys) and NCoR (Fig.…”

Section: Tbl1x Deficiencymentioning

confidence: 90%

Recent advances in research on isolated congenital central hypothyroidism

Tajima

Nakamura

Oguma

et al. 2019

Clin Pediatr Endocrinol

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. Congenital central hypothyroidism (C-CH) is caused by defects in the secretion of thyrotropin-releasing hormone (TRH) and/or TSH, leading to an impairment in the release of hormones from the thyroid. The causes of C-CH include congenital anomalies of the hypothalamic-pituitary regions and several genetic defects. In terms of endocrinology, C-CH is divided into two categories: ( 1 ) accompanied by another pituitary hormone deficiency and called combined pituitary hormone deficiency, and ( 2 ) isolated C-CH, showing mainly TSH deficiency. For isolated C-CH, a mutation in the TSH gene ( TSHB ) encoding the β-subunit of the protein was first found in 1990 by Japanese researchers, and thereafter several mutations in TSHB have been reported. Mutations in the thyrotropin-releasing hormone receptor gene ( TRHR ), as well as genetic defects in immunoglobulin superfamily 1 ( IGSF1 ), have also been identified. It was recently found that isolated C-CH is caused by mutations in transducin β-like 1 X-linked and insulin receptor substrate 4. It is noted that all patients with TSHB deficiency and some with IGSF1 deficiency show severe hypothyroidism soon after birth. Among the causes of C-CH, high frequency of mutations in IGSF1 is the most prevalent. This review focuses on recent findings on isolated C-CH.

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Section: Tbl1x Deficiencymentioning

confidence: 90%

Recent advances in research on isolated congenital central hypothyroidism

Tajima

Nakamura

Oguma

et al. 2019

Clin Pediatr Endocrinol

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“…The co-transfection of two TBL1X mutants identified in CeH patients (N365Y and Y458C) with NCoR1 showed impaired co-activation of the ligandindependent activation of the TRH promoter by TR. Of note, N365Y exerted significantly more potent inhibitory effects than Y458C on the ligand-independent stimulation of TRH and TSHβ gene promoters enhanced by NCoR1 (Takamizawa et al 2018). Impaired hearing in patients with TBL1X mutations is unexplained at this moment.…”

Section: Congenital Central Hypothyroidismmentioning

confidence: 92%

“…However, the molecular mechanisms by which mutant TBL1X proteins functionally disturb the negative feedback regulation of hypothalamic TRH and/ or pituitary TSHβ gene transcription by TH have not yet been elucidated. Takamizawa et al (Takamizawa et al 2018) reported that knockdown of endogenous TBL1X in N-1 cells (a hypothalamic neuronal cell line) using siRNA significantly attenuated the NCoR1-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of two TBL1X mutants identified in CeH patients (N365Y and Y458C) with NCoR1 showed impaired co-activation of the ligandindependent activation of the TRH promoter by TR.…”

Section: Congenital Central Hypothyroidismmentioning

confidence: 99%

The role of WD40 repeat-containing proteins in endocrine (dys)function

Bruinstroop

Hollenberg

et al. 2023

Journal of Molecular Endocrinology

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WD40 repeat-containing proteins play a key role in many cellular functions including signal transduction, protein degradation, and apoptosis. The WD40 domain is highly conserved, and its typical structure is a β-propeller consisting of 4-8 blades which probably serves as a scaffold for protein-protein interaction. Some WD40 repeat-containing proteins form part of the corepressor complex of nuclear hormone receptors, a family of ligand-dependent transcription factors that play a central role in the regulation of gene transcription. This explains their involvement in endocrine physiology and pathology. In the present review, we first touch upon the structure of WD40 repeat-containing proteins. Next, we describe our current understanding of the role of WD40 domain containing proteins in nuclear receptor signaling e.g. as corepressor or coactivator. In the final part of this review, we focus on WD40 domain containing proteins that are associated with endocrine pathologies. These pathologies vary from isolated dysfunction of one endocrine axis, e.g., congenital isolated central hypothyroidism, to more complex congenital syndromes comprising endocrine phenotypes, such as the Triple-A syndrome.

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“…However, genes involved in the negative feedback regulation of the HPT-axis like TSHB and TRH are negatively regulated by T3 which means that their transcription is increased in the absence of T3. It was shown that the c.1145_1147del p.(Asn382del), c.1246A>T p.(Asn416Tyr) and c.1526A>G p.(Tyr509Cys) (NM_005647.3) variants resulted in reduced stimulation of TSHB and TRH promoters in a hypothalamic cell line ( 45 , 46 ). Consequently, this may alter HPT-axis functioning to the point that the hypothalamus and pituitary are resistant to low TH levels, with a possible negative shift of the FT4 set-point.…”

Section: Etiologymentioning

confidence: 99%

Diagnosis and Management of Central Congenital Hypothyroidism

et al. 2021

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Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered (IGSF1, TBL1X, IRS4), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition.

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Transducin β-like 1, X-linked and nuclear receptor co-repressor cooperatively augment the ligand-independent stimulation of TRH and TSHβ gene promoters by thyroid hormone receptors

Cited by 7 publications

References 22 publications

Recent advances in research on isolated congenital central hypothyroidism

Recent advances in research on isolated congenital central hypothyroidism

The role of WD40 repeat-containing proteins in endocrine (dys)function

Diagnosis and Management of Central Congenital Hypothyroidism

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