Search for Abnormalities of Nuclear Corepressors, Coactivators, and a Coregulator in Families with Resistance to Thyroid Hormone without Mutations in Thyroid Hormone Receptor β or α Genes¹

Abstract

The syndrome of resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormones. Inheritance is usually autosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hormone receptor ␤ (TR␤) gene. Six of 65 families with the RTH phenotype studied in our laboratory had normal TR␤1 and TR␤2 gene sequences. Their clinical characteristics were not different from those of subjects with TR␤ gene mutations. Four of the 6 families were amenable to linkage analysis, and TR␣ involvement was excluded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators [NCoA-1 (SRC-1) and NCoA-3 (AIB-1)], 2 corepressors (NCoR and SMRT), and a coregulator (RXR␥). DNA was obtained from 8 affected subjects and 41 of 45 living first degree relatives. In 2 of the 4 families, the mode of inheritance could be determined by pedigree analysis and was found to be autosomal dominant. Linkage analyses were performed using polymorphic markers near or within the 5 candidate genes. When analyses were not informative or linkage could not be excluded, direct sequencing of the genes in question was performed.Involvement of NCoA-1 was excluded in all four families assuming autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were excluded in three and a role for RXR␥ was excluded in two of the four families. However, if the two families without proven dominant mode of inheritance were compound heterozygous, only the involvement of NCoA-1 could be excluded in both. Roles for NCoR, SMRT, and RXR␥ were excluded in one of these two families. Thus, NCoA-1 and RXR␥ genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA-1 and RXR␥ is the cause of RTH in mice. Involvement of other candidate genes in the mediation of thyroid hormone action as well as intracellular hormone transport needs to be explored in these families with non-TR␤, TR␣ RTH. (J Clin Endocrinol Metab 85: 3609 -3617, 2000)

Different responses to chronic somatostatin analogues in patients with central hyperthyroidism

“…As the circulating levels of TSH, FT4 and FT3 are similar in both groups of patients, several tests have been proposed in order to discriminate between the two disorders 2 . Unfortunately, none of the suggested tests retains the suitable sensitivity and specificity and diagnosis may frequently remain uncertain, 2,9,10 Indeed, clinical and radiological manifestations of a large pituitary adenoma definitely point to TSH‐oma diagnosis, but pituitary incidentalomas are very frequent in the general population 11 and pituitary tumours were also reported in patients with RTH 2,12–14 . Furthermore, many of the proposed tests (such as analysis of TRβ gene) can be performed only in specialized centres and the test provided with the highest diagnostic value, i.e.…”

Refractory depression in a patient with peripheral resistance to thyroid hormone (RTH) and the effect of triiodothyronine treatment

“…The absence of mutations in the coding regions of both genes raise the possibility that polymorphisms in other regions of TR isoforms, mutations in cofactors (NCoA-1, NCoA-2, NCoA-3) or dysregulation of its expression [30] may be involved in the peripheral RTH phenotype. Most thyroid hormone receptor isoforms, in presence of thyroid hormone, associate a coactivator protein, forming a complex that mediates the transcriptional activation.…”

Resistance to Thyroid Hormone Beta: A Focused Review

“…In 14% of individuals manifesting the RTHb phenotype no THRB mutations were identified. Rarely familial, they may be caused by mosaicism (11), whereas it has been postulated that mutations in enhancers, repressors or cofactors may be responsible for this subgroup of RTHb (12).…”