Contrasting Phenotypes in Resistance to Thyroid Hormone Alpha Correlate with Divergent Properties of Thyroid Hormone Receptor α1 Mutant Proteins

Background: Resistance to Thyroid Hormone alpha (RTHα), a disorder characterised by tissue-selective hypothyroidism and near-normal thyroid function tests due to thyroid receptor α gene mutations, is rare but probably underrecognised. We sought to correlate the clinical characteristics and response to thyroxine therapy in two adolescent RTHα patients with the properties of the THRA mutation, affecting both TRα1 and TRα2 proteins, they harboured. Methods: Clinical, auxological, biochemical and physiological parameters were assessed in each patient at baseline and after thyroxine therapy. Results: Heterozygous THRA mutations, occurring de novo, were identified in a 17yr old male (patient P1; A263V mutation), investigated for mild pubertal delay and a 15yr old male (patient P2; L274P mutation) with short stature (0.4th centile), skeletal dysplasia, dysmorphic facies and global developmental delay. Both individuals exhibited macrocephaly, delayed dentition and constipation together with a subnormal T4/T3 ratio, low reverse T3 levels and mild anaemia. When studied in vitro, A263V mutant TRα1 was transcriptionally impaired and inhibited the function of its wild type counterpart at low (0.01-10nM) T3 levels, with higher T3 concentrations (100nM-1µM) reversing dysfunction and such dominant negative inhibition. In contrast, L274P mutant TRα1 was transcriptionally inert, exerting significant dominant negative activity, only overcome with 10µM T3. Mirroring this, normal expression of KLF9, a TH-responsive target gene, was achieved in A263V mutation-containing peripheral blood mononuclear cells (PBMCs) following 1µM T3 exposure, but with markedly reduced expression levels in L274P mutation-containing PBMCs even with 10µM T3. Following thyroxine therapy, growth, body composition, dyspraxia and constipation improved in P1, whereas growth retardation and constipation in P2 were unchanged. Neither A263V or L274P mutations exhibited gain- or loss-of-function in the TRα2 background and no additional phenotype attributable to this was discerned. Conclusions: We correlate a milder clinical phenotype and favourable response to thyroxine therapy in an RTHα patient (P1) with heterozygosity for mutant TRα1 exhibiting partial, T3-reversible, loss-of-function. In contrast, a more severe clinical phenotype, refractory to hormone therapy, was evident in another case (P2), associated with severe, virtually irreversible, dysfunction of mutant TRα1.
Our research is supported by the Wellcome Trust (Investigator Award 095564/Z/11/Z to KC; Investigator Award 100237/Z/12/Z to JS) and NIHR Cambridge Biomedical Research Centre (CM, KC). JS is a Royal Society Wolfson Research Merit Award Holder.