Author:
Lanz Anna-Lisa,Erdem Serife,Ozcan Alper,Ceylaner Gulay,Cansever Murat,Ceylaner Serdar,Conca Raffaele,Magg Thomas,Acuto Oreste,Latour Sylvain,Klein Christoph,Patiroglu Turkan,Unal Ekrem,Eken Ahmet,Hauck Fabian
Abstract
AbstractLymphocyte-specific protein tyrosine kinase (LCK) is an SRC-family kinase critical for initiation and propagation of T-cell antigen receptor (TCR) signaling through phosphorylation of TCR-associated CD3 chains and recruited downstream molecules. Until now, only one case of profound T-cell immune deficiency with complete LCK deficiency [1] caused by a biallelic missense mutation (c.1022T>C, p.L341P) and three cases of incomplete LCK deficiency [2] caused by a biallelic splice site mutation (c.188-2A>G) have been described. Additionally, deregulated LCK expression has been associated with genetically undefined immune deficiencies and hematological malignancies. Here, we describe the second case of complete LCK deficiency in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immune deficiency. Whole exome sequencing (WES) revealed a novel pathogenic biallelic missense mutation in LCK (c.1393T>C, p.C465R), which led to the absence of LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Loss of conventional CD4+ and CD8+ αβT-cells and homeostatic T-cell expansion was accompanied by increased γδT-cell and Treg percentages. Surface CD4 and CD8 co-receptor expression was reduced in the patient T-cells, while the heterozygous mother had impaired CD4 and CD8 surface expression to a lesser extent. We conclude that complete LCK deficiency is characterized by profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder. CD4 and CD8 surface expression may be of value for early detection of mono- and/or biallelic LCK deficiency.
Funder
Else Kröner-Fresenius-Stiftung
Bundesministerium für Bildung und Forschung
Care-for-Rare Foundation
Türkiye Bilimler Akademisi
Bilim Akademisi
Erciyes Üniversitesi
Universitätsklinik München
Publisher
Springer Science and Business Media LLC
Subject
Immunology,Immunology and Allergy