Novel mutations in TACI (TNFRSF13B) causing common variable immunodeficiency

J Clin Immunol. 2009 Nov;29(6):777-85. doi: 10.1007/s10875-009-9317-5. Epub 2009 Jul 23.

Abstract

Introduction: Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. The disorder is also characterized by co-occurrence of autoimmune, lymphoproliferative, and granulomatous diseases. Mutations in the gene encoding TACI (Transmembrane Activator and CAML Interactor, TNFRSF13B) were previously found to be associated with CVID.

Materials and methods: We therefore sequenced TNFRSF13B gene in a cohort of 48 Iranian CVID patients. Expression of TACI and binding of A proliferation-inducing ligand (APRIL) were tested by FACS.

Results: We identified one patient with a homozygous G to T substitution in the TNFRSF13B gene at the splice site of intron 1 (c.61+1G>T), which abolished expression of the TACI molecule and binding capacity of APRIL. This represents the second CVID patient in the world with a complete absence of TACI expression. B cell lines from family members carrying the same mutation in a heterozygous form showed a reduced level of TACI expression and APRIL-binding capacity, suggesting a gene dosage effect. In addition, we found the previously recognized C104R and C172Y mutations in a heterozygous form in two patients with CVID and one, novel, heterozygous P42T mutation.

Conclusion: TACI mutations were observed in Iran CVID patients in a similar frequency as in other Caucasian populations. The novel mutations identified in this study support the notion of a crucial role for TACI in B cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism
  • Cell Differentiation
  • Cohort Studies
  • Common Variable Immunodeficiency / etiology
  • Common Variable Immunodeficiency / genetics*
  • Family Health
  • Female
  • Gene Dosage
  • Homozygote
  • Humans
  • Iran / epidemiology
  • Male
  • Mutation*
  • Pedigree
  • Protein Binding
  • Transmembrane Activator and CAML Interactor Protein / deficiency
  • Transmembrane Activator and CAML Interactor Protein / genetics*
  • Transmembrane Activator and CAML Interactor Protein / physiology*
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism

Substances

  • TNFRSF13B protein, human
  • Transmembrane Activator and CAML Interactor Protein
  • Tumor Necrosis Factor Ligand Superfamily Member 13