Direct genetic correction as a new method for diagnosis and molecular characterization of MHC class II deficiency

Matheux F., Ikinciogullari A., Zapata D., Barras E., Zufferey M., DOĞU E. F., ...More

MOLECULAR THERAPY, vol.6, no.6, pp.824-829, 2002 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 6 Issue: 6
  • Publication Date: 2002
  • Doi Number: 10.1006/mthe.2002.0804
  • Journal Name: MOLECULAR THERAPY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.824-829
  • Keywords: MHC class II deficiency, gene therapy, diagnostic test, lentiviral vector, human disease, bare lymphocyte syndrome, BARE LYMPHOCYTE SYNDROME, LENTIVIRAL VECTOR, IN-VIVO, EXPRESSION, TRANSACTIVATOR, COMPLEX, IMMUNODEFICIENCY, TRANSDUCTION, CIITA, CELLS
  • Ankara University Affiliated: No

Abstract

Major histocompatibility complex class II (MHCII) deficiency is a primary immunodeficiency resulting from defects in one of four different MHCII-specific transcription factors-CIITA, RFX5, RFXAP, and RFXANK. Despite this genetic heterogeneity, the phenotypical manifestations are homogeneous. It is frequently difficult to establish a definitive diagnosis of the disease on the basis of clinical and immunological criteria. Moreover, the phenotypical homogeneity precludes unambiguous identification of the regulatory gene that is affected. Identification of the four genes mutated in the disease has now allowed us to develop a rapid and straightforward diagnostic test for new MHCII-deficiency patients. This test is based on direct correction of the genetic defect by transduction of cells from patients with lentiviral vectors encoding CIITA, RFXANK, RFX5, or RFXAP. We have validated this approach by defining the molecular defects in two new patients. The RFXANK vector restored MHCII expression in a T cell line from one patient. The RFXAP vector corrected primary cells (PBL) from a second patient. Molecular analysis confirmed the presence of homozygous mutations in the RFXANK and RFXAP genes, respectively. Direct genetic correction represents a valuable tool for the diagnosis and classification of new MHCII-deficiency patients.