Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha 1 and TR alpha 2: clinical, biochemical, and genetic analyses of three related patients

Background The thyroid hormone receptor alpha gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)alpha 1 or a non-hormone-binding variant protein, TR alpha 2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TR alpha 1 and TR alpha 2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TR alpha 1, to delineate the relative roles of TR alpha 1 and TR alpha 2. Methods We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. Findings The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine: free tri-iodothyronine [T-3], low concentration of total reverse T-3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TR alpha 1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TR alpha 1 and TR alpha 2 proteins. The Ala263Val mutant TR alpha 1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TR alpha 2 matched its normal counterpart. In vitro, high concentrations of T-3 restored transcriptional activity of Ala263Val mutant TR alpha 1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T-3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. Interpretation TR alpha 1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA.