LCK was first reported in relation to autosomal recessive combined immunodeficiency (CID) due to LCK deficiency in 2012 (Hauck et al., PMID: 22985903). LCK deficiency has been reported in patients with typical symptoms of CID including decreased CD4+ T cells, failure to thrive, recurrent infections, hepatosplenomegaly, intestinal inflammation, and diarrhea. Affected individuals in one family were identified in adulthood with epidermodysplasia verruciformis, T-cell lymphopenia and a history of recurrent chest infections. Heterozygous carriers were reported to be unaffected. Five variants (missense, frameshift, and canonical splice site) that have been reported in five unrelated probands in five publications (PMIDs: 22985903, 38112969, 27087313, 37962568, 38100037) are included in this curation. Variants in this gene segregated with disease in four families. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by mouse model, rescue in cell culture model, expression, protein interaction, and biochemical function studies. LCK expression is restricted to lymphoid tissues and lymphocytes (PMID: 2416464). LCK was significantly reduced in T cells of a patient with CID (PMID: 9664084). LCK co-localizes with the pre-TCR and causes phosphorylation of the ITAMs of the CD3 epsilon, delta, and zeta chains and ZAP70 (PMID: 10952314). LCK activates DNA binding of STAT5A and STAT5B and LCK-deficient T-cells do not have activated STAT5 (PMID: 9880255). LCK-deficient T-cells have altered intracellular Ca2+ mobilization and tyrosine phosphorylation and expression of WT LCK restores TCR-mediated Ca2+ flux and tyrosine phosphorylation signals (PMID: 22985903). Mice with absent LCK had thymic atrophy, dramatically reduced double-positive (CD4+CD8+) thymocyte population, no detectable mature single-positive thymocytes, and very few peripheral T cells (PMID: 1579166). A hypomorphic phenotype with T-cell lymphopenia and survival to adulthood has also been reported (PMID: 27087313). This gene-disease pair was originally evaluated by the SCID-CID GCEP on 7/15/2022. It was reevaluated on 07/17/2025. As a result of this reevaluation, the classification changed from moderate to definitive with the addition of new case-level genetic evidence (PMID: 38112969, 37962568, 38100037).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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