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A mutation in the thyroid hormone receptor alpha gene

Elena Bochukova1, Nadia Schoenmakers, Maura Agostini

  • 1University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.

The New England Journal of Medicine
|December 16, 2011
PubMed

Insights

Thyroid hormone resistance can occur due to mutations in thyroid hormone receptor alpha (THRA). A child

Area of Science:

  • Endocrinology
  • Genetics
  • Molecular Biology

Background:

  • Thyroid hormones regulate growth and development via alpha (TRα) and beta (TRβ) receptors.
  • Defects in thyroid hormone signaling can lead to hypothyroidism with varying clinical severity.

Observation:

  • A child presented with severe hypothyroidism symptoms but only borderline thyroid hormone levels.
  • Whole-exome sequencing revealed a de novo heterozygous nonsense mutation in the THRA gene.

Findings:

  • The identified THRA mutation produced a mutant protein with dominant-negative inhibitory effects on the wild-type receptor.
  • This indicates a novel form of human thyroid hormone resistance mediated by defective TRα function.

Implications:

  • Substantiates the distinct roles of TRα and TRβ receptor subtypes in mediating thyroid hormone action.
  • Highlights the importance of considering genetic defects in thyroid hormone receptors for diagnosing unexplained hypothyroidism.
  • Provides insights into the molecular mechanisms of thyroid hormone resistance.

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