title: Minireview: Insights Into the Structural and Molecular Consequences of the TSH-β Mutation C105Vfs114X.
abstract: 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.
authors.affiliation: Institute of Experimental Pediatric Endocrinology (G.K., L.K., H.B.), Charité-Universitätsmedizin, Berlin, 13353 Germany; Institute of Experimental Endocrinology (J.K., L.S.), Charité-Universitätsmedizin Berlin, 13353 Germany; Trophogen, Inc (M.S.), Rockville, Maryland 20850; and Department of Pediatric Endocrinology and Diabetes (A.G.-K.), Charité-Universitätsmedizin, Berlin, 13353 Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.affiliation: Institute of Experimental Pediatric Endocrinology (G.K., L.K., H.B.), Charité-Universitätsmedizin, Berlin, 13353 Germany; Institute of Experimental Endocrinology (J.K., L.S.), Charité-Universitätsmedizin Berlin, 13353 Germany; Trophogen, Inc (M.S.), Rockville, Maryland 20850; and Department of Pediatric Endocrinology and Diabetes (A.G.-K.), Charité-Universitätsmedizin, Berlin, 13353 Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Kalveram
authors.affiliation: Institute of Experimental Pediatric Endocrinology (G.K., L.K., H.B.), Charité-Universitätsmedizin, Berlin, 13353 Germany; Institute of Experimental Endocrinology (J.K., L.S.), Charité-Universitätsmedizin Berlin, 13353 Germany; Trophogen, Inc (M.S.), Rockville, Maryland 20850; and Department of Pediatric Endocrinology and Diabetes (A.G.-K.), Charité-Universitätsmedizin, Berlin, 13353 Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.affiliation: Institute of Experimental Pediatric Endocrinology (G.K., L.K., H.B.), Charité-Universitätsmedizin, Berlin, 13353 Germany; Institute of Experimental Endocrinology (J.K., L.S.), Charité-Universitätsmedizin Berlin, 13353 Germany; Trophogen, Inc (M.S.), Rockville, Maryland 20850; and Department of Pediatric Endocrinology and Diabetes (A.G.-K.), Charité-Universitätsmedizin, Berlin, 13353 Germany.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Szkudlinski
authors.affiliation: Institute of Experimental Pediatric Endocrinology (G.K., L.K., H.B.), Charité-Universitätsmedizin, Berlin, 13353 Germany; Institute of Experimental Endocrinology (J.K., L.S.), Charité-Universitätsmedizin Berlin, 13353 Germany; Trophogen, Inc (M.S.), Rockville, Maryland 20850; and Department of Pediatric Endocrinology and Diabetes (A.G.-K.), Charité-Universitätsmedizin, Berlin, 13353 Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
authors.affiliation: Institute of Experimental Pediatric Endocrinology (G.K., L.K., H.B.), Charité-Universitätsmedizin, Berlin, 13353 Germany; Institute of Experimental Endocrinology (J.K., L.S.), Charité-Universitätsmedizin Berlin, 13353 Germany; Trophogen, Inc (M.S.), Rockville, Maryland 20850; and Department of Pediatric Endocrinology and Diabetes (A.G.-K.), Charité-Universitätsmedizin, Berlin, 13353 Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.affiliation: Institute of Experimental Pediatric Endocrinology (G.K., L.K., H.B.), Charité-Universitätsmedizin, Berlin, 13353 Germany; Institute of Experimental Endocrinology (J.K., L.S.), Charité-Universitätsmedizin Berlin, 13353 Germany; Trophogen, Inc (M.S.), Rockville, Maryland 20850; and Department of Pediatric Endocrinology and Diabetes (A.G.-K.), Charité-Universitätsmedizin, Berlin, 13353 Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters-Kieslich
mesh_terms: D006063:Chorionic Gonadotropin / Q000235:genetics / Q000378:metabolism; D005640:Follicle Stimulating Hormone / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D013972:Thyrotropin / Q000235:genetics* / Q000378:metabolism
chemical_list: D006063:Chorionic Gonadotropin; D006023:Glycoproteins; C458339:thyrostimulin; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013972:Thyrotropin