Two intriguing studies using novel models of thyroid hormone receptor alpha (THRA) mutations, which cause thyroid hormone resistance syndrome (RTH), were published in 2020. Krieger et al. [1] demonstrated the essential actions of thyroid hormone receptor alpha (TRα) on the normal development of the human cerebral cortex. The authors previously reported that adult patients with RTH had intellectual impairments, especially affecting nonverbal IQ and delayed sensorimotor processing [2]. Indeed, these findings were consistent with those of a mouse model with a mutant variant of TRα1, which showed a range of central nervous system abnormalities [3], but the cellular mechanisms of the impacts of THRA (the gene encoding TRα) on neural development remained unclear. Krieger et al. [1], using THRA mutant patient-derived induced pluripotent stem cell (iPS) models in combination with a quantitative lineage analysis, gene expression analysis, and novel assays of neuro-epithelium formation, showed that THRA regulates the balance between progenitor self-renewal and neurogenesis, thereby affecting the overall brain mass and especially the cortex. A structural modeling study of the ligand-binding domain of TRα1 demonstrated that the THRA mutation facilitates corepressor binding. Finally, a magnetic resonance imaging study of four patients harboring THRA mutations showed microcephaly with reduced cerebellar size and white matter density of the whole brain. Additionally, the authors suggested that their experimental method using patient-derived iPS is a good example of quantitative research in neurodevelopmental disorders.

Another study was published using a novel zebrafish model of RTH [4], which was generated by introducing dominant-negative germline mutations in both THRA alleles by the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 targeting system. Abnormalities in the heart system were observed at 35 days post-fertilization, in the juvenile period. Both anatomical abnormalities, including atrial dilatation and abnormal ventricular structures, and functional deficits such as reduced blood flow and reduced strength of contractions were observed. The key finding of this study was that the THRA mutation disrupted sarcomere organization, which gives cardiac muscles their striated appearance and critically affects heart function. The expression of genes associated with sarcomere assembly was suppressed, and structural abnormalities of sarcomere organization were found via transmission electron microscopy in the hearts of the mutant fish. This study provides an advanced understanding into the pathophysiology of bradycardia in RTH patients.

In the research field of iodothyronine deiodinase (Dio) signaling, an interesting study was published by Ferdous et al. [5]. In cardiomyocytes, they found that forkhead box O (FoxO) 1, not FoxO3, regulates the reciprocal regulation between Dio2 and Dio3, and that FoxO1 directly upregulates Dio2 genes and positively supports THRA-mediated hypertrophic growth of myocytes in neonatal rat ventricle. More importantly, FoxO1-Dio2 signaling plays an essential role in afterload-induced pathologic myocardial remodeling and activation of THRA in a transverse aortic restriction model of stress-induced cardiomyotrophy. This study highlights the importance of intracellular thyroid hormone homeostasis in the cellular response to pathologic stress.

A novel Dio1 mutation was reported by Franca et al. [6]. Two unrelated families had two missense pathogenic variants, resulting in p.Asn94Lys and p.Met201Ile, and showed abnormal thyroid hormone metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. This is the first report of an inherited Dio1 mutation in humans.