title: The BLNK adaptor protein has a nonredundant role in human B-cell differentiation.
abstract: BACKGROUND
  Expression of the pre-B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre-B-cell receptor result in early B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre-B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients with BLNK gene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified.
  
  
  METHODS
  B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiency in vitro and in vivo.
  
  
  RESULTS
  Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation in BLNK, which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre-BI- to pre-BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with the BLNK gene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes.
authors.affiliation: CIC-BT 502 Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Lagresle-Peyrou
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Faculté des Sciences de Luminy, Aix Marseille Université, UM2, Marseille, France; INSERM, U1104, Marseille, France; Centre National de la Recherche Scientifique, UMR7280, Marseille, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Millili
authors.affiliation: INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Luce
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Faculté des Sciences de Luminy, Aix Marseille Université, UM2, Marseille, France; INSERM, U1104, Marseille, France; Centre National de la Recherche Scientifique, UMR7280, Marseille, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Boned
authors.affiliation: CIC-BT 502 Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Hanem
authors.initials: H
authors.lastname: Sadek
authors.affiliation: CIC-BT 502 Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Rouiller
authors.affiliation: Unité d'Immunologie, Hématologie et Rhumatologie pédiatriques, Hôpital Necker-Enfants Malades, Paris, France; EA 3620, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Frange
authors.affiliation: Unité d'Immunologie, Hématologie et Rhumatologie pédiatriques, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Guilhem
authors.initials: G
authors.lastname: Cros
authors.affiliation: CIC-BT 502 Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.affiliation: INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France. Electronic address: isabelle.andre-schmutz@inserm.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: André-Schmutz
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Faculté des Sciences de Luminy, Aix Marseille Université, UM2, Marseille, France; INSERM, U1104, Marseille, France; Centre National de la Recherche Scientifique, UMR7280, Marseille, France. Electronic address: schiff@ciml.univ-mrs.fr.
authors.forename: Claudine
authors.initials: C
authors.lastname: Schiff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D015870:Gene Expression; D005816:Genetic Complementation Test; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D061905:Single-Domain Antibodies / Q000235:genetics / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D007145:Immunoglobulin kappa-Chains; D011498:Protein Precursors; D011947:Receptors, Antigen, B-Cell; D061905:Single-Domain Antibodies
keywords: Agammaglobulinemia; B-lymphocyte; BLNK protein; SCID-hu mouse; gene rearrangement; gene therapy; lymphopoiesis; pre–B-cell receptor