Sticht Heinrich, Hashemolhosseini Said
Institut für Biochemie, Friedrich-Alexander Universität Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany.
Med Hypotheses. 2006;67(3):482-7. doi: 10.1016/j.mehy.2006.01.062. Epub 2006 May 12.
Hypoparathyroidism, 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.
甲状旁腺功能减退症，无论是后天性还是遗传性的，都是一组由钙稳态缺陷引起的人类异质性疾病，临床上表现为低钙血症和高磷血症。据报道，甲状旁腺特异性转录因子GCMB的DNA结合域中的两个突变（R47L、G63S）与甲状旁腺功能减退症有关。这两个突变都会导致转录激活的丧失，其中R47L突变伴有DNA结合能力的丧失，而G63S突变则不伴有DNA结合能力的丧失。尽管它们在DNA结合能力方面存在这些差异，但野生型和突变型GCMB-DNA复合物的分子模型显示出一种共同的规则分子相互作用模式，这显然对GCM DNA结合域的完整性至关重要，并且会因各自的突变而改变。通过对所有已知的阻碍转录激活的GCM蛋白DNA结合域的生化突变进行研究，证实了该模型的重要性。所有这些突变都共享所提出的分子机制，因此可以通过我们的模型进行正确预测。这种机制上的共性使得能够预测另外21个残基，其中这些残基的突变可能会严重影响GCMB的转录激活能力，因此当患者存在这些突变时可能与疾病相关。
