title: Mutations in Igalpha (CD79a) result in a complete block in B-cell development.
abstract: Mutations in Btk, mu heavy chain, or the surrogate light chain account for 85-90% of patients with early onset hypogammaglobulinemia and absent B cells. The nature of the defect in the remaining patients is unknown. We screened 25 such patients for mutations in genes encoding components of the pre-B-cell receptor (pre-BCR) complex. A 2-year-old girl was found to have a homozygous splice defect in Igalpha, a transmembrane protein that forms part of the Igalpha/Igbeta signal-transduction module of the pre-BCR. Studies in mice suggest that the Igbeta component of the pre-BCR influences V-DJ rearrangement before cell-surface expression of mu heavy chain. To determine whether Igalpha plays a similar role, we compared B-cell development in an Igalpha-deficient patient with that seen in a mu heavy chain-deficient patient. By immunofluorescence, both patients had a complete block in B-cell development at the pro-B to pre-B transition; both patients also had an equivalent number and diversity of rearranged V-DJ sequences. These results indicate that mutations in Igalpha can be a cause of agammaglobulinemia. Furthermore, they suggest that Igalpha does not play a critical role in B-cell development until it is expressed, along with mu heavy chain, as part of the pre-BCR.
authors.affiliation: Departments of Immunology, Hematology/Oncology, and Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. yoshiyuki.minegishi@stjude.org
authors.forename: Y
authors.initials: Y
authors.lastname: Minegishi
authors.forename: E
authors.initials: E
authors.lastname: Coustan-Smith
authors.forename: L
authors.initials: L
authors.lastname: Rapalus
authors.forename: F
authors.initials: F
authors.lastname: Ersoy
authors.forename: D
authors.initials: D
authors.lastname: Campana
authors.forename: M E
authors.initials: ME
authors.lastname: Conley
mesh_terms: D000361:Agammaglobulinemia / Q000209:etiology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000502:physiology*; D051925:CD79 Antigens; D002675:Child, Preschool; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000502:physiology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015703:Antigens, CD; D051925:CD79 Antigens; C497881:CD79A protein, human; C497882:Cd79a protein, mouse; D007148:Immunoglobulin mu-Chains; D011947:Receptors, Antigen, B-Cell