ClinVar

In a 6-year-old girl of white European origin with congenital nongoitrous hypothyroidism (CHNG6; 614450), Bochukova et al. (2012) performed whole-exome sequencing and identified a de novo heterozygous 1207G-T transversion in the THRA gene, resulting in a glu403-to-ter (E403X) substitution, predicted to cause premature termination 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. Patient peripheral blood mononuclear cells demonstrated markedly reduced basal and triiodothyronine-induced expression of the thyroid hormone-responsive target gene KLF9 (602902) compared to wildtype. Two-hybrid interaction assays revealed strong recruitment of corepressors by E403X mutant TR-alpha, with failure of their hormone-dependent dissociation, and minimal triiodothyronine-dependent association with coactivator SRC1 (602691).

In a 14-year-old Polish girl with congenital nongoitrous hypothyroidism, Tylki-Szymanska et al. (2015) identified heterozygosity a c.1207G-T transversion (c.1207G-T, NM_199334) in the THRA gene, resulting in the E403X mutation. The mutation occurred de novo in the proband.