Structural analysis of disease-causing mutations in the P-subfamily of forkhead transcription factors.

Mutations in a number of forkhead transcription factors are associated with the development of inherited diseases in humans. Two closely related genes, FOXP2 and FOXP3, are implicated in two completely different human disorders. A point mutation in the forkhead domain of FOXP2 (R553H) is responsible for a severe speech and language disorder, while a series of missense mutations distributed over the forkhead domain of FOXP3 cause a fatal disorder called IPEX, characterized by immune dysregulation, polyendocrinopathy, and enteropathy. Homology model building techniques were used to generate atomic structures of FOXP2 and FOXP3, using the solution structures of the forkhead domain of the adipocyte-transcription factor FREAC-11 and AFX as templates. The impact of these disease-causing missense mutations on the three-dimensional structure, stability, and surface electrostatic charge distribution of the forkhead domains is examined here. The missense mutations R553H in FOXP2 and R397W in FOXP3 dramatically alter the electrostatic potentials of the molecular surface of their respective forkhead domains. Copyright 2004 Wiley-Liss, Inc.