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. 2017 Oct 20;6(10):e159. doi: 10.1038/cti.2017.41

Figure 1.

Figure 1

Novel de novo TCF3 mutation discovered in a CVID family carrying C104R TACI variant. (a) Digenic inheritance of TNFRSF13B (c.310T>C, C104R TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband’s son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation. The proband’s clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband’s parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (AD1, AD2) and helix-loop-helix (HLH) domains are shown. (d) E2A (E47) protein expression was assessed by western blotting of lysates following 30 min PMA/ionomycin stimulation of PBMCS in the kindred, as indicated (U, unstimulated; S, stimulated). (e) PBMCs from the proband (II.2) and healthy control (HC) individuals (n=2) were unstimulated, or stimulated with PMA+ionomycin for 30 or 60 min as indicated, and cell lysates were analysed for p105 phosphorylation (P-p105, Ser933), expression of p105 and p50 by western blotting. Beta-actin was used as a protein loading control. Results are representative of two independent experiments.