Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT

Baerbel Keller, Irina Zaidman, O. Sascha Yousefi, Dov Hershkovitz, Jerry Stein, Susanne Unger, Kristina Schachtrup, Mikael Sigvardsson, Amir A. Kuperman, Avraham Shaag, Wolfgang W. Schamel, Orly Elpeleg, Klaus Warnatz, Polina Stepensky

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54 Scopus citations


The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca2+ mobilization, residual T cells were able to induce Ca2+ influx and nuclear factor (NF) κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease.

Original languageEnglish
Pages (from-to)1185-1199
Number of pages15
JournalJournal of Experimental Medicine
Issue number7
StatePublished - 27 Jun 2016

Bibliographical note

Publisher Copyright:
© 2016 Keller et al.


B. Keller, O.S. Yousefi, S. Unger, W.W. Schamel, and K. Warnatz were supported by the German Federal Ministry of Education and Research (BMBF 01EO1303). P. Stepensky and K. Warnatz received funding from the Deutsche Forschungsgemeinschaft (Discovery and Evaluation of New Combined Immunodeficiency Disease Entities; grant DFG WA 1597/4-1). P. Stepensky was supported by a research grant from the joint fund of the Hebrew University and Hadassah Medical Center. This study was supported in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School).

FundersFunder number
Excellence Initiative of the German Research FoundationGSC-4
Hadassah Medical Organization
Deutsche ForschungsgemeinschaftDFG WA 1597/4-1
Bundesministerium für Bildung und Forschung01EO1303
Hebrew University of Jerusalem


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