Patients with a mutation in the thyroid hormone receptor α gene (THRA) that affects both the thyroid hormone receptor (TR) α1 and α2 protein variants have similar characteristics to patients with mutations affecting only the α1 variant, report researchers.
Similar to patients with mutations affecting TRα1, the three patients in this study had normal levels of circulating thyroid hormones, yet they developed symptoms suggestive of hypothyroidism in childhood, and treatment with thyroxine from an early age improved their symptoms.
Study author Krishna Chatterjee (Addenbrooke’s Hospital, Cambridge, UK) and co-workers say that awareness of the features of this condition “should enable early identification and treatment of other patients, which would be of particular importance should thyroxine treatment prove to be widely beneficial for this disorder.”
The three patients – a mother and two sons – had an alanine to valine substitution (Ala263Val) at codon 263 of THRA in the sequence common to both the TRα1 and TRα2 variants. This mutation was not present in the father or a third son, neither of whom had hypothyroidism symptoms.
Although they had normal thyroid hormone levels, when not treated with thyroxine for 6 weeks, the affected patients had abnormally low ratios of thyroxine to T3 (the active form of thyroid hormone) and low levels of reverse T3.
In vitro studies showed that the Ala263Val mutant TRα1 had significantly reduced binding to T3, and a reduced effect on the transcription of target genes, which was overcome at higher T3 concentrations.
In the patients, the Ala263Val mutant TRα1 was expressed along with normal TRα1, but its presence resulted in an overall reduction in the transcription of target genes (dominant-negative inhibition). However, high concentrations of T3 reversed this effect, both in vitro and in ex vivo patient-derived peripheral blood mononuclear cells, explaining why thyroxine treatment alleviated symptoms in the three patients.
By contrast, the Ala263Val mutant TRα2 appeared similar to the wild-type form, having little transcriptional activity and weak dominant-negative activity at high levels.
The three patients had delayed growth and development, constipation and macrocephaly, and both sons had motor incoordination. All patients had a thickened skull vault and, when not taking thyroxine, they had greatly reduced resting energy expenditure with increased levels of skeletal muscle creatine kinase. When they restarted thyroxine, their resting energy expenditure increased, low-density lipoprotein levels fell, and creatine kinase decreased in two patients.
The researchers also note that their patients had “numerous skin tags and moles”, similar to patients with TRα1 mutations. Although also present in the general population, they suggest this “might be an additional characteristic of the disorder, although its absence would not exclude diagnosis.”
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