A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone

Abstract

This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRα1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHα.

Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

“…6A) and assess both the influence of the mutation on TET3 interaction and dominant-negative property. TRα1 E403X (11) and TRα1 N359Y (12) have been found in two patients, and TRα1 L400R is lethal in a mouse knock-in model (13). As expected TRα N359Y and TRα1 L400R , but not TRα1 E403X , interacted with TET3-Cat (Fig.…”

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

“…Although both the TRα mutations identified in the present patients also involve the TRα2 isoform, no added phenotype attributable to this could be discerned, and no gain or loss of function could be documented with the introduction of these amino acid changes into the TRα2 background. Thus, with the exception of a single case in which unusual skeletal and other features were recorded ( 7 ), no readily recognizable additional phenotypes could be identified in 14 individuals harboring mutations common to both TRα1 and TRα2 proteins ( 6 , 8 , 9 ). However, the possibility cannot be discounted of a mutation in TRα2 being associated with a phenotype that is either so subtle or of variable penetrance that it can only be discerned in a larger cohort of RTHα cases.…”

“…Thirteen different THRA mutations in 19 cases from 14 families have been recorded hitherto ( 1–9 ): nine mutations, selectively involving the divergent carboxyterminal domain of thyroid hormone receptor α1 (TRα1), are generally more deleterious exhibiting severe loss of function; four missense mutations are associated with variably impaired function of TRα1, with higher concentrations of triiodothyronine (T3) reversing mutant receptor dysfunction both in vitro ( 8 , 9 ) and in mutation-containing patient-derived cells studied ex vivo ( 6 ). These missense mutations also involve the non-TH binding TRα2 protein, with no discernible gain or loss of function or added phenotypes attributable to mutant α2 in virtually all cases ( 6 , 8 , 9 ), except a single patient who exhibited a constellation of unusual anomalies ( 7 ).…”

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

“…The affected individuals have slightly abnormal thyroid function tests with low to normal free T 4 , slightly elevated free T 3 , reduced rT 3 , and normal TSH levels, but display clear phenotypic characteristics of hypothyroidism with growth and developmental retardation, skeletal dysplasia, marked constipation (diarrhea in one case), and cognitive impairment. Identified mutations in THRA gene led to expression of either a truncated THRA completely unable to bind T 3 or mutations decreasing affinity to T 3 and transcriptional activity showing dominant-negative features (Bochukova et al 2012, Espiard et al 2015, Moran et al 2014, Moran et al 2013, Tylki-Szymanska et al 2015, van Mullem et al 2012. Cases of RTH in the absence of mutations in the THRB or THRA genes were also identified suggesting that mutations in co-regulator protein might be involved; however, human subjects with this type of RTH are yet to be identified (Reutrakul et al 2000, Weiss et al 1996.…”