A common structural mechanism underlying GCMB mutations that cause hypoparathyroidism

SummaryHypoparathyroidism, either of acquired or inherited origin, is a heterogenous group of human disorders caused by a defective calcium homeostasis clinically known as hypocalcemia and hyperphosphatemia.Two mutations (R47L, G63S) in the DNA binding domain of the parathyroid-specific transcription factor GCMB have been reported to be linked to hypoparathyroidism. Both mutations cause a loss of transactivation either with (R47L) or without (G63S) a concomitant loss of DNA binding. Despite these differences with respect to their DNA binding ability, molecular modeling of the wild type and mutant GCMB–DNA complexes reveals a common regular pattern of molecular interactions which is apparently crucial for the integrity of the GCM DNA binding domain and is altered by the respective mutations.The significance of this model is substantiated from an investigation of all biochemically known mutations of the DNA binding domain of GCM proteins that impede transactivation. All of them share the proposed molecular mechanism and thus can be predicted correctly by our model. This mechanistic commonness allows the prediction of 21 additional residues of which mutation might critically affect the transactivating ability of GCMB and thus might be linked to disease when present in patients.