Immunodeficiency in a Patient with 22q11.2 Distal Deletion Syndrome and a p.Ala7dup Variant in the MAPK1 Gene

Abstract

The genetic basis for sporadic immunodeficiency in patients with 22q11.2 distal deletion syndrome is unknown. We report an adult with a type 1 (D-F) 22q11.2 distal deletion syndrome and recurrent severe infections due to herpes zoster virus, presenting mild T cell lymphopenia and diminished frequency of naive CD4⁺ T cells, but increased frequencies of central, effector, and terminally differentiated memory T cells. Antigen-specific CD4⁺ and CD8⁺ T cells to influenza, rotavirus, and SEB were conserved in the patient, but responses to tetanus toxoid were temporarily undetectable. Exomic sequencing identified the c.20_22dupCGG (NM_002745.4) variant in the remaining MAPK1 gene of the patient, which adds 1 alanine to the polyalanine amino-terminal tract of the protein (p.Ala7dup). The mother, unlike the father, was heterozygote for the variant. Western blot analysis with the patient's activated PBMCs showed a 91% reduction in the MAPK1 protein. Further studies will be necessary to determine whether or not the variant present in the remaining MAPK1 gene of the patient is pathogenic.

Keywords: 22q11.2 distal (D–F) deletion syndrome; Immunodeficiency; MAPK1; T lymphocytes.

Fig. 1

Proliferation and intracellular cytokine T cells assays in response to polyclonal SEB stimulation, influenza, TT, and rotavirus. Frequency of CD4⁺ (A) and CD8⁺ T cells (B) that proliferate (CFSE^-), producing IL-2 (CFSE^-IL-2⁺) or IFNγ (CFSE^-IFNγ⁺) of the patients and their respective matched controls after stimulation with SEB, influenza (FLU), TT, and rotavirus (RV). Patient 1 and patient 2 correspond to the patients with 22q11.2PDS and 22q11.2DDS, respectively.

Fig. 2

Phenotype and frequencies of cytokine-producing CD4⁺ T cells in response to SEB and TT of the patient with 22q11.2DDS two weeks after TT vaccination, in comparison with T cells from a healthy control. A Left dot plots show frequencies of live CD3⁺CD4⁺ T cells expressing CD45RA and CCR7. Middle and right dot plots represent frequencies of live CD3⁺CD4⁺ T cells producing IFNγ and TNFα (with the expression of IL-2 being represented for each event by the color bar on the right) after stimulation with control medium or TT. B Boolean analysis of CD4⁺ T cells that produce IL-2, IFN-γ, or TNF-α, individually or in combination, after stimulation with medium, SEB, and TT in the control volunteer (top) and patient (bottom).

Fig. 3

A-D MAPK1 protein from activated PBMCs is decreased in the patient with 22q11.2DDS. A PBMCs from the patient with 22q11.2DDS and the control volunteer were unstimulated or stimulated with PMA for 5 and 10 min. MAPK1/MAPK3 protein was detected using the total ERK2/ERK1 mouse monoclonal antibody and phospho-specific rabbit polyclonal antibodies. A secondary antibody labeled with horseradish peroxidase was used for detection by chemoluminescence. Densitometry of total MAPK1 (B), phosorylated MAPK1 (C), and MAPK3 (D) were normalized to β-tubulin.