title: Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B-cell dysfunction in patients with Smith-Magenis syndrome.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Chinen
authors.forename: Monica
authors.initials: M
authors.lastname: Martinez-Gallo
authors.forename: Wenli
authors.initials: W
authors.lastname: Gu
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cols
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.forename: Lin
authors.initials: L
authors.lastname: Radigan
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.forename: Marjorie
authors.initials: M
authors.lastname: Withers
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015331:Cohort Studies; D003564:Cytidine Deaminase / Q000235:genetics; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D056724:Immunity, Humoral; D007223:Infant; D008297:Male; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D058496:Smith-Magenis Syndrome / Q000235:genetics* / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics*; D055815:Young Adult; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D012333:RNA, Messenger; C495371:TLR9 protein, human; C108467:TNFRSF13B protein, human; D051217:Toll-Like Receptor 9; D053303:Transmembrane Activator and CAML Interactor Protein; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase