Immune deficiencies, infection, and systemic immune disorders
Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

https://doi.org/10.1016/j.jaci.2012.07.029Get rights and content

Background

Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte–specific protein tyrosine kinase (Lck) is a key component of the TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency.

Objective

We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy.

Methods

Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported.

Results

The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4+ T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca2+ mobilization in response to TCR stimulation.

Conclusion

We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity.

Section snippets

Methods

Details of the materials and methods used in this study are provided in the Methods section in this article's Online Repository at www.jacionline.org. We obtained written informed consent for participation in the study from the parents of the patient. This study was approved by the institutional review board at Necker-Enfants Malades Hospital, and all experiments were carried out in accordance with the Helsinki Declaration.

Clinical features

We examined a child conceived by means of in vitro fertilization and born at term to healthy nonconsanguineous parents from France. Her birth weight was normal, and she was vaccinated at birth with BCG with no adverse effect. She had received 4 heptavalent conjugate vaccines against pneumococcus and 4 pentavalent vaccinations against Haemophilus influenzae type b, diphtheria, Bordetella pertussis, tetanus, and poliovirus at the ages of 2, 4, 6, and 14 months. She also received 2 immunizations

Discussion

We report here the first case of human LCK deficiency caused by complete maternal UPD of chromosome 1, which harbored the mutated LCK gene. UPD accounts for this recessive form of pediatric primary immunodeficiency in this patient, with the LCK germinal mutation being absent in the father and present in the patient's mother in the heterozygous state. UPD is defined as the inheritance of a pair of duplicated chromosomes from a single parent, and it is associated with 2 principal types of

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  • Cited by (0)

    Supported by grants from INSERM, Agence Nationale de la Recherche (ANR-08-MIEN-012-01, France), and the European Research Council (ERC-2009-AdG_20090506 no. FP7-249816). S.L. is a senior scientist at the Centre National de la Recherche Scientifique (France) and F.H. is a clinician at the University Children's Hospital of Dresden (Germany) and holds fellowships from the German Research Council/DFG (HA 5967/1-1) and the Fondation IMAGINE (France). S.G. holds a fellowship from the Ministère de la Recherche and l'Ecole Polytechnique (France) and the Fondation ARC pour la Recherche sur le Cancer (ARC) (France). E.M. is supported by the ANR (France). D.M. received a Robert A. Good/Jeffrey Modell fellowship.

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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