title: Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity.
abstract: Complete lack of function of the tyrosine kinase ZAP70 in humans results in a severe immunodeficiency, characterized by a lack of mature CD8(+) T cells and non-functional CD4(+) T cells. We report herein an immunodeficiency with an inherited hypomorphic mutation of ZAP70 due to a single G-to-A substitution in a non-coding intron. This mutation introduces a new acceptor splice site and allows low levels of normal alternative splicing and of WT ZAP70 expression. This partial deficiency results in a compromised TCR signaling that was totally restored by increased expression of ZAP70, demonstrating that defective activation of the patient T cells was indeed caused by the low level of ZAP70 expression. This partial ZAP70 deficiency was associated with an attenuated clinical and immunological phenotype as compared with complete ZAP70 deficiency. CD4(+) helper T-cell populations including, follicular helper T cells, Th1, Th17 and Treg were detected in the blood. Finally, the patient had no manifestation of autoimmunity suggesting that the T-cell tolerogenic functions were not compromised, in contrast to what has been observed in mice carrying hypomorphic mutations of Zap70. This report extends the phenotype spectrum of ZAP70 deficiency with a residual function of ZAP70.
authors: Centre d'Etude des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, EU, Paris, France.
authors: Capucine
authors: C
authors: Picard
authors: Stéphanie
authors: S
authors: Dogniaux
authors: Karine
authors: K
authors: Chemin
authors: Zofia
authors: Z
authors: Maciorowski
authors: Annick
authors: A
authors: Lim
authors: Fabienne
authors: F
authors: Mazerolles
authors: Frédéric
authors: F
authors: Rieux-Laucat
authors: Marie-Claude
authors: MC
authors: Stolzenberg
authors: Marianne
authors: M
authors: Debre
authors: Jean-Paul
authors: JP
authors: Magny
authors: Françoise
authors: F
authors: Le Deist
authors: Alain
authors: A
authors: Fischer
authors: Claire
authors: C
authors: Hivroz
mesh_terms: D000595:Amino Acid Sequence; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D002118:Calcium