Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA)

Abstract

THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended.

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

“…Although other RTH␣ patients display some bone malformations (8), these have been much less visible. Impaired ossification, without obvious malformation, is observed in THRA knockout mice (17,18) and mouse models of RTH␣ (19).…”

“…The first mutation (TR␣1 E403X ) was discovered in 2012 after whole exome sequencing (WES) was done in a 6-year-old girl with growth impairment (4). This initial description prompted the report of several other mutations: TR␣1 F397fs406X (5), TR␣1 A382fs388X (6), TR␣1 A263V (7), TR␣1 C392X , TR␣1 P398R , and again TR␣1 E403X in a different family (8). Finally, a large exome sequencing program aimed at identifying genetic causes of autism identified TR␣1 R384C in one patient (9).…”

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.…”

The In Vitro Functional Impairment of Thyroid Hormone Receptor Alpha 1 Isoform Mutants Is Mainly Dictated by Reduced Ligand Sensitivity

“…These mutations can be categorized into two groups based on the type of mutation. The first group consists of truncating mutations caused by nonsense or frameshift mutations that create premature stop codons and shorten the length of the LBD (8,9,(12)(13)(14). This structural alteration completely abolishes T3 affinity and T3-induced transcriptional activity of TRa1.…”

“…This structural alteration completely abolishes T3 affinity and T3-induced transcriptional activity of TRa1. The second group consists of missense mutations that result in single amino acid substitutions in the LBD (10,(13)(14)(15)(16)(17)(18)(19)(20). These mutant receptors can still bind T3, but with a lower affinity than wild-type (WT) receptors.…”