Endocrine Abstracts

Patients with resistance to thyroid hormone β (RTHβ) often display a neurocognitive phenotype, but the underlying biological defects have not been characterized. The predominant receptor isoform expressed in brain tissue is TRα1 leading to the assumption that this receptor accounts for most of the T3 effects. Nevertheless, TRα and TRβ are both expressed in brain therefore our study aims to understand the impact of a mutant THRβ on TH action in the brain. The peripheral blood mononuclear cells (PBMCs) were expanded and reprogrammed into induced pluripotent stem cells (iPSCs) from one RTHβ patient, harbouring p.M442V variant and affected with anxiety and severe short memory impairment, and one healthy control. The generated iPSCs were then differentiated into cortical neurons, using previously validated protocol. By qRT-PCR analysis we observed that both THRβ1 and THRβ2 are expressed in the differentiated cortical progenitors and neurons in the ratio of 1:2 respect to THRα, thus confirming the possible implication of THRβ in the neurological derangements of the RTHβ patient. We found a higher expression of MCT8 and a lower expression of in the patient cortical neurons compared to control at all different developmental days (rosette, neurons at 79 and 110 days of maturation). Surprisingly, a significant reduction was detected in the expression of the vesicular glutamate transporters (VGLUT1 and VGLUT2) in the RTHβ patient, while the vesicular GABA transporter (VGAT) and GABA decarboxylase 1 (GAD1) expression remained unchanged, in keeping with the known role of THRα during the GABAergic neuron development. Interestingly, in animal models VGLUT1 deficiency causes impaired visual attention, anxiety and depression, and VGLUT1/2 expression correlates with learning and memory. In conclusion, we report the unprecedented generation of cortical neurons from one RTHβ patient. Interestingly, the THRβ is expressed and appears involved in cortical neuron development. This model will be useful to understand the molecular basis underlying the neurological manifestations of RTHβ patients.