title: Novel compound heterozygous mutations in ZAP70 in a Chinese patient with leaky severe combined immunodeficiency disorder.
abstract: In humans, the complete lack of tyrosine kinase ZAP70 function results in combined immunodeficiency (CID), with abnormal thymic development and defective T cell receptor (TCR) signaling of peripheral T cells, characterized by the selective absence of CD8+T cells. So far, 15 unique ZAP70 mutations have been identified in approximately 20 patients with CID, with variable clinical presentations. Herein, we report the first case from China of novel compound heterozygous mutations in ZAP70 (c.598-599delCT, p.L200fsX28; c.847 C>T, R283H). The patient suffered from early-onset and recurrent infections, but showed normal growth and development without signs of failure to thrive, thus presenting as leaky SCID. The patient also had clinical manifestations of autoimmunity, such as eczematous skin lesion, inflammatory bowel disease (IBD), and intractable diarrhea, suggesting compromised T cell tolerogenic functions. Residual ZAP70 expression was identified. Immunological analysis revealed the selective absence of CD8+T cells in the periphery and the presence of CD4+T cells that failed to respond to phytohemagglutinin. Stimulation with lectin from pokeweed mitogen also failed to stimulate B cell proliferation in the patient. The frequency of Tfhs and Tregs in the patient was lower compared with the normal reference. Compared with the age-matched healthy control, the level of IL-17 was higher and the levels of IFN-γ, IL-4, and IL-21 were lower. Infants with selected CD8 deficiency and severe autoimmune disorders or exaggerated inflammation should be screened for ZAP70 deficiency.
authors.affiliation: Research Center for Immunologic and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Research Center for Immunologic and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Research Center for Immunologic and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Research Center for Immunologic and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Research Center for Immunologic and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Chen
authors.affiliation: Research Center for Immunologic and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Xiu-Hong
authors.initials: XH
authors.lastname: Xue
authors.affiliation: Clinical Laboratory Center, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Zhou
authors.affiliation: Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Tang
authors.affiliation: Research Center for Immunologic and Infectious Diseases, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.|Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhao
authors.affiliation: Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. zzy510214@126.com.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D002681:China; D016207:Cytokines / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008213:Lymphocyte Activation; D008297:Male; D009154:Mutation / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human
keywords: Autoimmunity; CD8 deficiency; Severe combined immunodeficiency; Signal transduction; T cell receptor; ZAP70