TY - JOUR
T1 - Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B-cell dysfunction in patients with Smith-Magenis syndrome
AU - Chinen, Javier
AU - Martinez-Gallo, Monica
AU - Gu, Wenli
AU - Cols, Montserrat
AU - Cerutti, Andrea
AU - Radigan, Lin
AU - Zhang, Li
AU - Potocki, Lorraine
AU - Withers, Marjorie
AU - Lupski, James R.
AU - Cunningham-Rundles, Charlotte
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/6
Y1 - 2011/6
N2 - Background: Heterozygous deleterious mutations in the gene encoding the tumor necrosis factor receptor superfamily member 13b (TNFRSF13B), or transmembrane activator and CAML interactor (TACI), have been associated with the development of common variable immunodeficiency. Smith-Magenis syndrome (SMS) is a genetic disorder characterized by developmental delay, behavioral disturbances, craniofacial anomalies, and recurrent respiratory tract infections. Eighty percent of subjects have a chromosome 17p11.2 microdeletion, which includes TACI. The remaining subjects have mutations sparing this gene. Objective: We examined TACI protein expression and function in patients with SMS to define the role of TACI haploinsufficiency in B-cell function. Methods: We studied TACI expression and function in a cohort of 29 patients with SMS. Results: In patients with SMS with only 1 TACI allele, we found decreased B-cell extracellular and intracellular expression of TACI, reduced binding of a proliferation-inducing ligand, and decreased TACI-induced expression of activation-induced cytidine deaminase mRNA, but these were normal for cells from patients with SMS and 2 TACI alleles. Impaired upregulation of B-cell surface TACI expression by a Toll-like receptor 9 agonist was also observed in cells from patients with 1 TACI allele. Gene sequence analysis of the remaining TACI allele revealed common polymorphisms, with the exception of 1 patient with an amino acid change of uncertain significance. Patients with SMS with the lowest TACI expression had significantly reduced antibody responses to pneumococcal vaccine serotypes. Discussion: Our findings suggest that haploinsufficiency of the TACI gene results in humoral immune dysfunction, highlighting the role of genomic copy number variants in complex traits.
AB - Background: Heterozygous deleterious mutations in the gene encoding the tumor necrosis factor receptor superfamily member 13b (TNFRSF13B), or transmembrane activator and CAML interactor (TACI), have been associated with the development of common variable immunodeficiency. Smith-Magenis syndrome (SMS) is a genetic disorder characterized by developmental delay, behavioral disturbances, craniofacial anomalies, and recurrent respiratory tract infections. Eighty percent of subjects have a chromosome 17p11.2 microdeletion, which includes TACI. The remaining subjects have mutations sparing this gene. Objective: We examined TACI protein expression and function in patients with SMS to define the role of TACI haploinsufficiency in B-cell function. Methods: We studied TACI expression and function in a cohort of 29 patients with SMS. Results: In patients with SMS with only 1 TACI allele, we found decreased B-cell extracellular and intracellular expression of TACI, reduced binding of a proliferation-inducing ligand, and decreased TACI-induced expression of activation-induced cytidine deaminase mRNA, but these were normal for cells from patients with SMS and 2 TACI alleles. Impaired upregulation of B-cell surface TACI expression by a Toll-like receptor 9 agonist was also observed in cells from patients with 1 TACI allele. Gene sequence analysis of the remaining TACI allele revealed common polymorphisms, with the exception of 1 patient with an amino acid change of uncertain significance. Patients with SMS with the lowest TACI expression had significantly reduced antibody responses to pneumococcal vaccine serotypes. Discussion: Our findings suggest that haploinsufficiency of the TACI gene results in humoral immune dysfunction, highlighting the role of genomic copy number variants in complex traits.
KW - B cell
KW - common variable immunodeficiency
KW - gene haploinsufficiency
KW - humoral immunity
KW - Smith-Magenis syndrome
KW - transmembrane activator and CAML interactor
UR - http://www.scopus.com/inward/record.url?scp=79957816860&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2011.02.046
DO - 10.1016/j.jaci.2011.02.046
M3 - Article
C2 - 21514638
AN - SCOPUS:79957816860
VL - 127
SP - 1579
EP - 1586
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 6
ER -