New Pathogenic Thyrotropin Receptor Mutations Decipher Differentiated Activity Switching at a Conserved Helix 6 Motif of Family A GPCR

Abstract

Until now, only naturally occurring constitutively activating mutations in TSHR TMH6 have been reported, but here we present the first pathogenic inactivating mutation (Pro639Leu). Our data are indicative of differentiated regulation of Gs and Gq signaling at particular TMH6 positions, but without any effects on TSHR oligomer constellation. Details of signaling modulation by each mutant at positions 636(6.47) and 639(6.50) help us to understand high conservation of these amino acids in family A GPCR. Described molecular (pathogenic) mechanisms are likely not unique for TSHR.