ClinGen Dosage Sensitivity Curation Page

THRA

  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Changes in THRA have been associated with nongoitrous congenital hypothyroidism. Evidence suggests that reported mutations act in a dominant negative manner. Buchokova et al. (2012) performed whole-exome sequencing on a 6-year-old girl of white European origin with congenital nongoitrous hypothyroidism and identified a de novo heterozygous E403X substitution in THRA, predicted to cause premature truncation with loss of the C-terminal alpha-helix. The mutation was not found in published normal genomes and exomes or in 200 ethnically matched control alleles. Functional analysis demonstrated that the mutant receptor did not activate a thyroid hormone-responsive reporter gene and mediated substantial repression of basal promoter activity, consistent with negligible binding of radiolabeled triiodothyronine to mutant TR-alpha. Coexpression studies showed that the E403X receptor strongly inhibited transcriptional activity by wildtype TR-alpha in a dominant-negative manner (PMID: 22168587). van Mullem et al. (2012) studied a father and daughter with congenital nongoitrous hypothyroidism and identified a frameshift predicted to result in premature termination (F397fs406X) in THRA. The mutation was not found in the unaffected mother, in 300 Caucasian controls, or in public databases. Transfection studies showed that the mutant receptor does not respond to stimulation by T3, and also exerts a strong dominant-negative effect on wildtype THRA (PMID: 22494134).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity