title: A Novel Mutation in a Critical Region for the Methyl Donor Binding in DNMT3B Causes Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome (ICF).
abstract: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is an extremely rare autosomal recessive disease. The immune phenotype is characterized by hypogammaglobulinemia in the presence of B cells. T cell lymphopenia also develops in some patients. We sought to further investigate the immune defect in an ICF patient with a novel missense mutation in DNMT3B and a severe phenotype.
  
  
  
  Patient lymphocytes were examined for subset counts, immunoglobulin levels, T and B cell de novo production (via excision circles) and receptor repertoire diversity. Mutated DNMT3B protein structure was modeled to assess the effect of a mutation located outside of the catalytic region on protein function.
  
  
  
  A novel homozygous missense mutation, Ala585Thr, was found in DNMT3B. The patient had decreased B cell counts with hypogammaglobulinemia, and normal T cell counts. CD4+T cells decreased over time, leading to an inversion of the CD4+to CD8+ratio. Excision circle copy numbers were normal, signifying normal de novo lymphocyte production, but the ratio between naïve and total B cells was low, indicating decreased in vivo B cell replication. T and B cell receptor repertoires displayed normal diversity. Computerized modeling of the mutated Ala585 residue suggested reduced thermostability, possibly affecting the enzyme kinetics.
  
  
  
  Our results highlight the existence of a T cell defect that develops over time in ICF patient, in addition to the known B cell dysfunction. With intravenous immunoglobulin (IVIG) treatment ameliorating the B cell defect, the extent of CD4+lymphopenia may determine the severity of ICF immunodeficiency.
authors.affiliation: Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Edmond and Lily Safra Children's Hospital, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Rechavi
authors.affiliation: Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Atar
authors.initials: A
authors.lastname: Lev
authors.affiliation: Cancer Research Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Cancer Research Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Barel
authors.affiliation: Cancer Research Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Kol
authors.affiliation: Cancer Research Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Sarit Farage
authors.initials: SF
authors.lastname: Barhom
authors.affiliation: Edmond and Lily Safra Children's Hospital, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Pode-Shakked
authors.affiliation: Edmond and Lily Safra Children's Hospital, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Metabolic Disease Unit, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel. rsomech@hotmail.com.|Edmond and Lily Safra Children's Hospital, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel. rsomech@hotmail.com.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel. rsomech@hotmail.com.
authors.forename: Raz
authors.initials: R
authors.lastname: Somech
authors.affiliation: Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel. amos.simon@sheba.health.gov.il.|Cancer Research Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel. amos.simon@sheba.health.gov.il.|Institute of Hematology, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel. amos.simon@sheba.health.gov.il.|Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Ramat Gan, Israel. amos.simon@sheba.health.gov.il.
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002503:Centromere / Q000235:genetics*; D002675:Child, Preschool; D043171:Chromosomal Instability / Q000235:genetics* / Q000276:immunology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D005145:Face / Q000002:abnormalities*; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D007223:Infant; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B
keywords: DNMT3B; ICF; Immunodeficiency; KREC; TREC; centromeric instability and facial anomalies syndrome; hypogammaglobulinemia