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Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome


BACKGROUND: Mutations in the SP110 gene result in infantile onset of the autosomal recessive primary immunodeficiency disease veno-occlusive disease with immunodeficiency syndrome (VODI), which is characterized by hypogammaglobulinemia, T-cell dysfunction, and a high frequency of hepatic veno-occlusive disease. OBJECTIVES: We sought to further characterize the clinical features, B-lineage cellular immunologic findings, and molecular pathogenesis of this disorder in 9 patients with new diagnoses, including 4 novel mutations from families of Italian, Hispanic, and Arabic ethnic origin. METHODS: Methods used include clinical review; Sanger DNA sequencing of the SP110 gene; determination of transfected mutant protein function by using immunofluorescent studies in Hep-2 cells; quantitation of B-cell subsets by means of flow cytometry; assessments of B-cell function after stimulation with CD40 ligand, IL-21, or both; and differential gene expression array studies of EBV-transformed B cells. RESULTS: We confirm the major diagnostic criteria and the clinical utility of SP110 mutation testing for the diagnosis of VODI. Analysis of 4 new alleles confirms that VODI is caused by reduced functional SP110 protein levels. Detailed B-cell immunophenotyping demonstrated that Sp110 deficiency compromises the ability of human B cells to respond to T cell-dependent stimuli and differentiate into immunoglobulin-secreting cells in vitro. Expression microarray studies have identified pathways involved in B-lymphocyte differentiation and macrophage function. CONCLUSION: These studies show that a range of mutations in SP110 that cause decreased SP110 protein levels and impaired late B-cell differentiation cause VODI and that the condition is not restricted to the Lebanese population. J Allergy Clin Immunol. 2012 Sep;130(3):735-742.e6. Epub 2012 May 21.

Type Journal
ISBN 1097-6825 (Electronic) 0091-6749 (Linking)
Authors Cliffe, S. T.; Bloch, D. B.; Suryani, S.; Kamsteeg, E. J.; Avery, D. T.; Palendira, U.; Church, J. A.; Wainstein, B. K.; Trizzino, A.; Lefranc, G.; Akatcherian, C.; Megarbane, A.; Gilissen, C.; Moshous, D.; Reichenbach, J.; Misbah, S.; Salzer, U.; Abinun, M.; Ong, P. Y.; Stepensky, P.; Ruga, E.; Ziegler, J. B.; Wong, M.; Tangye, S. G.; Lindeman, R.; Buckley, M. F.; Roscioli, T.;
Published Date 2012-01-01
Published Volume 130
Published Issue 3
Published Pages 735-742 e6
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version