THRA – Resistance to Thyroid Hormone Syndrome

Resistance to thyroid hormone (RTH) syndrome is characterized by elevated circulating thyroid hormones with unsuppressed TSH and tissue-specific hyposensitivity. Heterozygous variants in THRA, encoding the thyroid hormone receptor α1, underlie RTHα, a distinct form of RTH with predominant peripheral hypothyroid features and near-normal thyroid function tests. THRA variants are autosomal dominant and lead to a spectrum of clinical manifestations including growth delay, developmental delay, constipation, short stature, macrocephaly, and neurocognitive impairment (PMID:25670821).

Genetic evidence supports a strong gene–disease association. Six unrelated probands from five families with truncating and missense THRA variants exhibited consistent phenotypes of mild hypothyroidism, growth retardation, and altered FT4/FT3 ratios, with segregation in two multiplex pedigrees (PMID:25670821). A representative variant is c.1075A>T (p.Asn359Tyr) identified de novo in a patient with congenital anemia, bone malformations, and neurodevelopmental delay (PMID:26037512). Variants include missense changes in the ligand-binding domain and frameshift/truncating alleles, all exerting dominant-negative effects on wild-type receptor function.

Functional assays confirm dominant-negative pathogenicity. Knock-in mice harboring the PV frameshift mutation recapitulate RTHα with impaired growth, delayed bone development, dysregulated pituitary-thyroid axis, and neurobehavioral defects (PMID:15862829). Zebrafish embryos expressing human mutant TRα1 show tissue-specific defects in cardiovascular, craniofacial, and neural development reversible by high T3 dosing (PMID:27809680). In vitro studies demonstrate impaired T3 binding, anomalous corepressor retention, and failure to release NCoR upon hormone stimulation.

No robust conflicting evidence has been reported. Genotype–phenotype correlations reveal that variants with partially reversible dominant-negative activity (e.g., p.Ala263Val) may respond to thyroxine therapy, whereas severely dysfunctional alleles (e.g., p.Leu274Pro) show limited treatment benefit.

Integration of genetic and experimental data yields a definitive molecular mechanism—dominant-negative interference of TRα1 leading to tissue-specific resistance. THRA variant analysis should be incorporated into diagnostic panels for patients with unexplained growth delay, neurodevelopmental symptoms, and an altered FT4/FT3 ratio. Early identification enables tailored thyroid hormone supplementation, which may improve growth and neurologic outcomes.

Key Take-home: THRA mutations cause autosomal dominant RTHα via dominant-negative receptor dysfunction; genetic testing guides diagnosis and informs therapeutic T4/T3 dosing.

References

• Journal of medical genetics • 2015 • Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA) PMID:25670821
• The Journal of clinical endocrinology and metabolism • 2015 • A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone. PMID:26037512
• Steroids • 2005 • Isoform-dependent actions of thyroid hormone nuclear receptors: lessons from knockin mutant mice. PMID:15862829
• Thyroid • 2017 • In vivo Functional Consequences of Human THRA Variants Expressed in the Zebrafish. PMID:27809680

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