Figure 1.

Localization of disease-related missense variations and mutations in TCF4.A, representation of TCF4 isoforms B¯ and A¯. The colored boxes show conserved protein domains. The dark-grey region in TCF4-A¯ represents a nonfunctional partial CE domain (according to Herbst and Kolligs (37)) and the blue region in TCF4-A¯ shows unique amino acids encoded by exon 10a of TCF4 (34). Nuclear localization signals are shown on top. Disease-related missense substitutions analyzed in the present article are shown below the protein isoforms and marked according to the color code below. Missense mutations and variations have been associated with mild-to-moderate intellectual disability (MMID; N90S and R114K, marked green), schizophrenia (SCZ; S102C, P156T, F211L, P299S, A315V, and G428V, marked blue), Rett-like syndrome (RTT-like; S253R, marked orange), and Pitt-Hopkins syndrome (PTHS; R569W, N585D, and A587P, marked purple). B, the position of missense mutations in TCF4 bHLH identified in PTHS patients to date. Novel PTHS-associated missense mutations are shown in purple. The protein regions are indicated with lines on top, and NLS-2 is marked with a dashed underline. The bHLH beginning (567) and end (625) coordinates are in the context of TCF4-B⁺. C, ribbon drawing of TCF4 structure model (5) showing bHLH homodimer bound to DNA (dark blue). Pink and green structures indicate the ‘nonspecific’ and ‘specific’ TCF4 subunit, respectively. The novel missense substitutions identified in PTHS patients are colored yellow and indicated with arrows. A, motif A; bHLH, basic helix-loop-helix; C, motif C; CE, conserved element; AD1, AD2, and AD3, transcription activation domain; NLS, nuclear localization signal; Rep, repression domain; TCF4, transcription factor 4.