A novel thyroid hormone receptor-beta mutation that fails to bind nuclear receptor corepressor in a patient as an apparent cause of severe, predominantly pituitary resistance to thyroid hormone
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Dosyalar
Tarih
2006
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Endocrine Soc
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Context: Resistance to thyroid hormone ( RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone ( TH). Objective: We report a newborn who presented with severe RTH ( Mkar) with serum TSH 1500 mU/ liter and free T-3 greater than 50 p(M) ( normal 3.1 - 9.4) and free T-4 25.3 pM ( normal 12 - 22). We hypothesized that the RTH was due to reduced ligand binding and/ or abnormal interaction with nuclear cofactors. Design: These were prospective in vivo and in vitro studies. Setting: The study was conducted at a tertiary care university hospital. Patients: Patients included a newborn child and two other subjects with RTH. Intervention: The effect of various TH- lowering agents in the subject with RTH was studied. In vitro studies including EMSA and mammalian two- hybrid assay as well as in vitro transfection studies were conducted. Main Outcome Measures: Sequencing of the TH receptor ( TR)beta and in vitro measurements of receptor- cofactor interaction were measured. Results: Sequencing of the TR beta demonstrated a de novo heterozygous mutation, 1590_ 1591insT, resulting in a frameshift producing a mutant TR beta( mutTR)-beta with a 28- amino acid ( aa) nonsense sequence and 2- amino acid carboxyl- terminal extension. The Mkar mutation was evaluated in comparison to three other TR beta frameshift mutations in the carboxyl terminus. EMSA demonstrated that the Mkar mutTR beta 1 had impaired ability to recruit nuclear receptor corepressor but intact association with silencing mediator of retinoid and thyroid receptor ( SMRT). Conclusion: Our data suggest that alterations in codons 436 - 453 in helix 11 result in significantly diminished association with nuclear eceptor corepressor but not SMRT. This novel mutTR beta demonstrates nuclear corepressor specificity that results in severe predominantly pituitary RTH due to impaired release of SMRT.
Açıklama
Anahtar Kelimeler
Amino Acid Sequence, DNA-Binding Proteins, Electrophoretic Mobility Shift Assay, Genes, Mammalia
Kaynak
Journal Of Clinical Endocrinology & Metabolism
WoS Q Değeri
N/A
Scopus Q Değeri
Q1
Cilt
91
Sayı
5
