scholarly journals Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene

2004 ◽  
Vol 150 (6) ◽  
pp. 819-823 ◽  
Author(s):  
K Frank-Raue ◽  
A Lorenz ◽  
C Haag ◽  
W Hoppner ◽  
HU Boll ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Intellectual Development ◽  
Thyroid Hormone Receptor ◽  
Receptor Gene ◽  
Signs And Symptoms ◽  
Severe Form ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Negative Effect ◽  
Beta Gene

Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta).We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S (1123T-->G) was present either on both alleles or in a hemizygous form with complete deletion of the second allele. The I280S mutation was recently reported in a heterozygous patient. The severe phenotype with seriously impaired intellectual development, hyperkinetic behaviour, tachycardia, hearing and visual impairment is probably due to the dominant negative effect of the I280S mutant protein and the absence of any functional TR-beta.

scholarly journals Thyroid Hormone Resistant Syndrome

2020 ◽  
pp. 6-10
Author(s):  
Karo Gyurjian ◽  
Vishwanath Venketaraman
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Receptor Gene ◽  
Signs And Symptoms ◽  
Thyroid Stimulating Hormone ◽  
Hormone Resistance ◽  
Thyroid Receptor ◽  
Thyroid Hormone Levels ◽  
Beta Gene ◽  
Receptor Beta

Thyroid hormone resistance (THR), also known as resistance to thyroid hormone (RTH), is an inherited condition characterized by reduced end-organ responsiveness to thyroid hormone, caused by mutations in the thyroid hormone receptor gene. Patients typically present with elevated thyroid hormone levels (T3 and T4) with normal, or slightly elevated thyroid-stimulating hormone (TSH) levels.1 In a majority of cases, the disease is caused by a mutation in the thyroid receptor beta (TR-beta) gene. Patients can present with signs and symptoms of hypothyroidism or hyperthyroidism or can be asymptomatic. We present a case of a 16-year-old male who was referred for endocrinologic evaluation after abnormal findings in the thyroid function panel.

scholarly journals PGC-1α regulates the isoform mRNA ratio of the alternatively spliced thyroid hormone receptor α transcript

2006 ◽  
Vol 37 (2) ◽  
pp. 251-257 ◽  
Author(s):  
D C Thijssen-Timmer ◽  
M Platvoet-Ter Schiphorst ◽  
J Kwakkel ◽  
R Emter ◽  
A Kralli ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Rna Processing ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Mrna Levels ◽  
Negative Effect ◽  
Alternatively Spliced ◽  
Thyroid Hormone Receptor Α

Transcripts derived from the thyroid hormone receptor α (TRα) gene are alternatively spliced resulting in a functional receptor TRα1 and a non-T3-binding variant TRα2 that can exert a dominant negative effect on the transactivation functions of other TRs. There is evidence that the ratio of TRα isoform transcripts can be modulated and here, we investigate whether the PPARγ co-activator α (PGC-1α) has an effect on this splicing process. PGC-1α was discovered not only as a transcriptional co-activator, but also has certain motifs characteristic of splicing factors. We demonstrate that PGC-1α alters the ratio of endogenously expressed TRα isoform transcripts in HepG2 cells, by decreasing TRα1 mRNA levels twofold. This change in isoform ratio is accompanied by a decrease in 5′-deiodinase expression, whereas no differences were found in TRβ1 expression. Deletion of the RNA-processing domain of PGC-1α abrogated the effect on the TRα splicing, whereas expression of only the RNA-processing domain favored TRα1 expression. PGC-1α showed a similar effect on the splicing of a TRα minigene containing only the last four exons and introns of the TRα gene. These data suggest that PGC-1α is involved in the RNA processing of TRα transcripts.

scholarly journals The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

2011 ◽  
Vol 211 (1) ◽  
pp. 39-46 ◽  
Author(s):  
L A Santiago ◽  
D A Santiago ◽  
L C Faustino ◽  
A Cordeiro ◽  
P C Lisboa ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Thyroid Hormone Receptor ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Hepatic Glycogen ◽  
Dominant Negative Mutation ◽  
Hepatic Glucose

Mice bearing the genomic mutation Δ337T on the thyroid hormone receptor β (TRβ) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRβΔ337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRβΔ337T mice exhibited normal glycemia and were more tolerant to an i.p. glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRβΔ337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration. In addition, hepatic glycogen content was lower in homozygous TRβΔ337T mice than in wild type. Collectively, the data suggest that TRβΔ337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-γ coactivator 1α, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRβ, reproducing a hypothyroid phenotype. In conclusion, mice carrying the Δ337T-dominant negative mutation on the TRβ are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.

scholarly journals A Japanese single-center experience of the efficacy and safety of enzyme replacement therapy in childhood-onset hypophosphatasia

2021 ◽  
Author(s):  
Yohei Sugiyama ◽  
Taijiro Watanabe ◽  
Makiko Tajika ◽  
Tetsuro Matsuhashi ◽  
Masaru Shimura ◽  
...  
Keyword(s):  
Severe Form ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Single Center ◽  
Childhood Onset ◽  
Enzyme Replacement ◽  
Heterozygous Variant ◽  
Negative Effect ◽  
Bone Abnormalities ◽  
Low Serum

Abstract BackgroundHypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The phenotype of HPP is widely diverse from the perinatal severe form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to impaired development of the lungs and severe hypomineralization of the bones. Enzyme replacement therapy (ERT) using asfotase alfa was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of ERT experience in ten cases of childhood-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 years [7.6–12.5] years; 60% male). This is the largest study of a single-center cohort describing the clinical course of HPP patients treated with ERT in Asia. ResultsOne case of perinatal lethal form of HPP, two cases of perinatal benign form, six cases of childhood form, and one case of odontohypophophatasia were observed. The most common symptom at onset was bone abnormalities. All patients had low serum ALP levels as compared to the age-matched reference range before the commencement of ERT. All HPP patients responded to ERT without serious adverse effects. Genetic analysis showed that eight out of ten patients had compound heterozygosity; two patients had only one heterozygous variant. In this study, two patients had a heterozygous variant of ALPL and responded to ERT, although the variants did not have the dominant-negative effect. ConclusionsERT may be effective in patients with symptoms of HPP even with only one pathogenic variant of ALPL without dominant-negative effect. Early diagnosis based on symptoms such as bone abnormalities or low serum alkaline phosphatase levels might be essential for early treatment and can contribute to better prognosis.

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