Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.

Adams, Matthew; Matthews, Charles H.; Collingwood, Trevor N.; Tone, Yukiko; Beck‐Peccoz, Paolo; Chatterjee, Krishna

doi:10.1172/jci117362

Cited by 217 publications

(129 citation statements)

References 60 publications

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“…Codon 429 of TR-␤, located adjacent to the 3Ј end of the 9th heptad of the TR dimerization region, is conserved among related members of the nuclear hormone receptor superfamily. A point mutation in codon 429, converting an arginine to a glutamine (CGG to CAG) in 1 allele, has been described by our group as well as others as a naturally occurring mutation among patients with clinically apparent CRTH (31)(32)(33)(34). We have previously demonstrated that the R429Q mutation does not impair the ability to bind ligand (32).…”

Section: Resultsmentioning

confidence: 97%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Resistance to thyroid hormone (RTH) is most often due to point mutations in the ␤-isoform of the thyroid hormone (TH) receptor (TR-␤). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-␤ locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T 3 replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T 3 treatment failed to normally suppress these levels. T3 treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T 3 treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.corepressor ͉ homodimer ͉ negative regulation ͉ resistance to thyroid hormone T hyroid-stimulating hormone (thyrotropin or TSH) is a heterodimeric glycoprotein consisting of 2 non-covalently linked protein subunits (TSH-␣ and TSH-␤), synthesized in the pituitary thyrotroph, which regulates the thyroid. TSH-releasing hormone (TRH) is synthesized in the paraventricular nucleus of the hypothalamus and released into the portal circulation, where it regulates the synthesis and glycosylation pattern (bioactivity) of pituitary TSH. The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback involving thyroid hormones (THs) (T 4 and T 3 ), which are produced by the thyroid gland. The major negative regulator of TSH secretion is T 3 , which directly inhibits the transcription of the TSH-␣ and -␤ subunit genes (1-5) and TRH (6-8).TH action is mediated by different isoforms of the TH receptor (TR), which are members of the nuclear receptor superfamily of ligand-modulated transcription factors. Two genes, by alternative splicing and transcriptional start site utilization, express the known ligand-binding TR isoforms, TR-␣1, TR-␤1, TR-␤2, and TR-␤3. Negative regulation of the HPT axis is principally mediated by the ␤ isoform of the TR (9-13).On genes with a positive TH response element, TR interacts with corepressor proteins (CoRs) in the absence of ligand, and this...

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Section: Resultsmentioning

confidence: 97%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…3). The mutant (mut) TRβ molecules have either reduced affinity for T 3 [39,41], or abnormal interaction with one of the cofactors involved in TH action [40,42].…”

Section: Geneticsmentioning

confidence: 99%

Syndromes of Reduced Sensitivity to Thyroid Hormone

Weiss

Dumitrescu

Refetoff

2010

Genetic Diagnosis of Endocrine Disorders

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“…This may be explained by individual differences in the distribution of TRa and TRb in the tissues (2,3,26). Moreover, variations in expression of the mutant TRb and the extent to which it inhibits the wild-type TRb (4,27) or other nuclear receptors (28) may contribute to this diversity.…”

Section: Discussionmentioning

confidence: 99%

Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor mutation

Kvistad

Løvås²,

Boman³

et al. 2004

European Journal of Endocrinology

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Objective: Thyroid hormone resistance (RTH) is characterised by variable tissue hyporesponsiveness to thyroid hormone. The disorder is usually caused by mutations in the thyroid hormone receptor beta (TRb). We describe a large family with this disorder. Subjects and measurement: We identified 36 family members with RTH in four generations by screening relatives of patients with the diagnosis. The diagnosis was verified by identification of a mutation in the thyroid hormone receptor beta (TRb) gene. Symptoms, clinical findings and laboratory tests of 29 affected individuals were compared with those of 16 first-degree relatives. Results: Bone maturation in children with RTH was delayed. The height was lower both in children and in adults with RTH than in the controls. Children with RTH had lower birth weight than the controls, particularly when the condition was inherited from the father. We did not observe increased prevalence of neuropsychological symptoms associated with RTH in this family. Palpitations and increased pulse rate indicated mild cardiac hyperthyroidism. Direct sequence analysis of the TRb gene revealed a novel point mutation, a heterozygous transition c.1031G . C in exon 9 theoretically substituting Gly344Ala. Conclusions: We found evidence of skeletal tissue hypothyroidism that resulted in permanent growth retardation from prenatal to adult life. We found substantial variations in thyroid hormone levels and clinical presentation, but most individuals were without symptoms of thyroid disorder. European Journal of Endocrinology 150 425-430

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Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.

Abstract: Resistance to thyroid hormone (RTH), with elevated serum free thyroid hormones and nonsuppressed thyrotropin levels, is either relatively asymptomatic, suggesting a generalized disorder (GRTH) Invest. 1994. 94:506-515.)

Cited by 217 publications

References 60 publications

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Syndromes of Reduced Sensitivity to Thyroid Hormone

Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor mutation

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