title: Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency.
abstract: 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 Ca(2+) mobilization in response to TCR stimulation.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hauck
authors.forename: Clotilde
authors.initials: C
authors.lastname: Randriamampita
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Martin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gerart
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Zosia
authors.initials: Z
authors.lastname: Maciorowski
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.forename: Sébastien
authors.initials: S
authors.lastname: Heritier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.forename: Fréderic
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: André
authors.initials: A
authors.lastname: Veillette
authors.forename: Claire
authors.initials: C
authors.lastname: Hivroz
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D020013:Calcium Signaling / Q000235:genetics; D002478:Cells, Cultured; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005602:France; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000235:genetics*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D011110:Polymorphism, Genetic; D000081207:Primary Immunodeficiency Diseases; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018344:T-Lymphocytopenia, Idiopathic CD4-Positive / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)