title: Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome.
abstract: BACKGROUND
  Mutations in the SP110 gene result in infantile onset of the autosomal recessive primary immunodeficiency disease veno-occlusive disease with immunodeficiency syndrome (VODI), which is characterized by hypogammaglobulinemia, T-cell dysfunction, and a high frequency of hepatic veno-occlusive disease.
  
  
  OBJECTIVE
  We sought to further characterize the clinical features, B-lineage cellular immunologic findings, and molecular pathogenesis of this disorder in 9 patients with new diagnoses, including 4 novel mutations from families of Italian, Hispanic, and Arabic ethnic origin.
  
  
  METHODS
  Methods used include clinical review; Sanger DNA sequencing of the SP110 gene; determination of transfected mutant protein function by using immunofluorescent studies in Hep-2 cells; quantitation of B-cell subsets by means of flow cytometry; assessments of B-cell function after stimulation with CD40 ligand, IL-21, or both; and differential gene expression array studies of EBV-transformed B cells.
  
  
  RESULTS
  We confirm the major diagnostic criteria and the clinical utility of SP110 mutation testing for the diagnosis of VODI. Analysis of 4 new alleles confirms that VODI is caused by reduced functional SP110 protein levels. Detailed B-cell immunophenotyping demonstrated that Sp110 deficiency compromises the ability of human B cells to respond to T cell-dependent stimuli and differentiate into immunoglobulin-secreting cells in vitro. Expression microarray studies have identified pathways involved in B-lymphocyte differentiation and macrophage function.
  
  
  CONCLUSIONS
  These studies show that a range of mutations in SP110 that cause decreased SP110 protein levels and impaired late B-cell differentiation cause VODI and that the condition is not restricted to the Lebanese population.
authors.affiliation: Department of Haematology and Genetics, Prince of Wales Hospital, Sydney, Australia.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Cliffe
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bloch
authors.forename: Santi
authors.initials: S
authors.lastname: Suryani
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Umaimainthan
authors.initials: U
authors.lastname: Palendira
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Church
authors.forename: Brynn K
authors.initials: BK
authors.lastname: Wainstein
authors.forename: Antonino
authors.initials: A
authors.lastname: Trizzino
authors.forename: Gérard
authors.initials: G
authors.lastname: Lefranc
authors.forename: Carlo
authors.initials: C
authors.lastname: Akatcherian
authors.forename: André
authors.initials: A
authors.lastname: Megarbané
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
authors.forename: Siraj
authors.initials: S
authors.lastname: Misbah
authors.forename: Uli
authors.initials: U
authors.lastname: Salzer
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.forename: Peck Y
authors.initials: PY
authors.lastname: Ong
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.forename: Ezia
authors.initials: E
authors.lastname: Ruga
authors.forename: John B
authors.initials: JB
authors.lastname: Ziegler
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Robert
authors.initials: R
authors.lastname: Lindeman
authors.forename: Michael F
authors.initials: MF
authors.lastname: Buckley
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D006504:Hepatic Veno-Occlusive Disease / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D016130:Immunophenotyping; D007223:Infant; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*
chemical_list: D016756:Immunoglobulins, Intravenous; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; C412425:Sp110 protein, human