Contrasting phenotypes in Resistance to Thyroid Hormone α correlate with divergent properties of thyroid hormone receptor α1 mutant proteins.

Contrasting phenotypes in Resistance to Thyroid Hormone α correlate with divergent properties of thyroid hormone receptor α1 mutant proteins.

Thyroid. 2017 May 04;:

Authors: Moran C, Agostini M, McGowan A, Schoenmakers E, Fairall L, Lyons G, Rajanayagam O, Watson L, Offiah AC, Barton JS, Price S, Schwabe JW, Chatterjee VK

Abstract
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 <i>THRA</i> 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 <i>THRA</i> mutations, occurring <i>de novo</i>, 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<i> in vitro</i>, 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.

PMID: 28471274 [PubMed - as supplied by publisher]

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