Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
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Acknowledgments
We thank the patient’s family for their cooperation. Raz Somech is supported by the Jeffrey Modell Foundation (JMF).
Authorship Contributions
B.P.S, Y.A. and R.S. diagnosed, followed, and treated the patient.
E.R., A.L., R.S, and A.J.S. conceived and designed the experiments.
E.R., A.L. A.J.S., and S.F.B. performed the experiments.
E.E., O.B., and N.K., performed the bioinformatic analysis
E.R., A.L., E.E., R.S., and A.J.S. analyzed and interpreted results and wrote the paper.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflict of Interest
The authors declare that they have no conflict of interests.
Additional information
Erez Rechavi and Atar Lev have equally contributed to the study.
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Rechavi, E., Lev, A., Eyal, E. et al. A Novel Mutation in a Critical Region for the Methyl Donor Binding in DNMT3B Causes Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome (ICF). J Clin Immunol 36, 801–809 (2016). https://doi.org/10.1007/s10875-016-0340-z
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DOI: https://doi.org/10.1007/s10875-016-0340-z