Minireview: Insights Into the Structural and Molecular Consequences of the TSH-β Mutation C105Vfs114X.

Naturally occurring thyrotropin (TSH) mutations are rare, which is also the case for the homologous heterodimeric glycoprotein hormones (GPHs) follitropin (FSH), lutropin (LH), and choriogonadotropin (CG). Patients with TSH-inactivating mutations present with central congenital hypothyroidism. Here, we summarize insights into the most frequent loss-of-function β-subunit of TSH mutation C105Vfs114X, which is associated with isolated TSH deficiency. This review will address the following question. What is currently known on the molecular background of this TSH variant on a protein level? It has not yet been clarified how C105Vfs114X causes early symptoms in affected patients, which are comparably severe to those observed in newborns lacking any functional thyroid tissue (athyreosis). To better understand the mechanisms of this mutant, we have summarized published reports and complemented this information with a structural perspective on GPHs. By including the ancestral TSH receptor agonist thyrostimulin and pathogenic mutations reported for FSH, LH, and choriogonadotropin in the analysis, insightful structure function and evolutionary restrictions become apparent. However, comparisons of immunogenicity and bioactivity of different GPH variants is hindered by a lack of consensus for functional analysis and the diversity of used GPH assays. Accordingly, relevant gaps of knowledge concerning details of GPH mutation-related effects are identified and highlighted in this review. These issues are of general importance as several previous and recent studies point towards the high impact of GPH variants in differential signaling regulation at GPH receptors (GPHRs), both endogenously and under diseased conditions. Further improvement in this area is of decisive importance for the development of novel targeted therapies.