A mutation in the thyroid hormone receptor alpha gene.

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.

• 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)

Chemical References

• Codon, Nonsense
• Thyroid Hormone Receptors alpha
• Thyroid Hormones
• Triiodothyronine
• Thyroxine

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)