title: Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.
abstract: X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency syndrome associated with the inability to control Epstein-Barr virus (EBV), lymphoma, and hypogammaglobulinemia. XLP is caused by mutations in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), or in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP). Here we report a patient with recurrent respiratory tract infections and early onset agammaglobulinemia who carried a unique disease-causing intronic loss-of-function mutation in SH2D1A. The intronic mutation affected SH2D1A gene transcription but not mRNA splicing, and led to markedly reduced level of SAP protein. Despite undetectable serum immunoglobulins, the patient's B cells replicated and differentiated into antibody producing cells normally in vitro.
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA. rechermike@uhbs.ch
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Fried
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Michela
authors.initials: M
authors.lastname: Rizzini
authors.forename: Francesco
authors.initials: F
authors.lastname: Frugoni
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.forename: Divij
authors.initials: D
authors.lastname: Mathew
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.forename: Christoph
authors.initials: C
authors.lastname: Hess
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000361:Agammaglobulinemia / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D007438:Introns / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
chemical_list: D016756:Immunoglobulins, Intravenous; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein