Abstract |
Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.
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Authors | Elena Bochukova, Nadia Schoenmakers, Maura Agostini, Erik Schoenmakers, Odelia Rajanayagam, Julia M Keogh, Elana Henning, Jana Reinemund, Evelien Gevers, Margarita Sarri, Kate Downes, Amaka Offiah, Assunta Albanese, David Halsall, John W R Schwabe, Murray Bain, Keith Lindley, Francesco Muntoni, Faraneh Vargha-Khadem, Faraneh Vargha Khadem, Mehul Dattani, I Sadaf Farooqi, Mark Gurnell, Krishna Chatterjee |
Journal | The New England journal of medicine
(N Engl J Med)
Vol. 366
Issue 3
Pg. 243-9
(Jan 19 2012)
ISSN: 1533-4406 [Electronic] United States |
PMID | 22168587
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Codon, Nonsense
- Thyroid Hormone Receptors alpha
- Thyroid Hormones
- Triiodothyronine
- Thyroxine
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Topics |
- Child
- Codon, Nonsense
- Female
- Growth Disorders
(drug therapy, genetics)
- Heterozygote
- Humans
- Hypothyroidism
(drug therapy, genetics)
- Models, Molecular
- Protein Conformation
- Thyroid Hormone Receptors alpha
(chemistry, genetics)
- Thyroid Hormones
(blood)
- Thyroxine
(blood, therapeutic use)
- Triiodothyronine
(blood)
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