Abnormal differentiation of B cells and megakaryocytes in Roifman syndrome

Publication date: Available online 31 January 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Jessica Heremans, Josselyn E. Garcia-Perez, Ernest Turro, Susan M. Schlenner, Ingele Casteels, Roxanne Collin, Francis de Zegher, Daniel Greene, Stephanie Humblet-Baron, Sylvie Lesage, Patrick Matthys, Christopher J. Penkett, Karen Put, Kathleen Stirrups, Chantal Thys, Chris Van Geet, Erika Van Nieuwenhove, Carine Wouters, Isabelle Meyts, Kathleen Freson, Adrian Liston
BackgroundRoifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia and, in some patients, thrombocytopenia. Compound heterozygous variants in small nuclear RNA gene RNU4ATAC, necessary for U12-type intron splicing, were recently identified to drive Roifman syndrome.ObjectiveWe studied three patients from two unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC to gain insights in the mechanisms behind this disorder.MethodsWe systematically profiled the immunological and hematological compartments of the three Roifman patients and performed RNA sequencing to unravel important splicing defects in both cell lineages.ResultsThe patients exhibited a dramatic reduction in B cells, with differentiation halted at the transitional B cell stage. Despite abundant BAFF availability, development past this BAFF-dependent stage was crippled, with disturbed minor splicing of the critical MAPK1 signaling component. In the hematological compartment, Roifman patients demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Roifman platelets were rounder, with elevated tubulin and actin levels, and contained increased alpha and dense granule markers. Significant minor intron retention in 354 megakaryocyte genes was observed, including DIAPH1 and HPS1, genes known to regulate platelet and dense granule formation, respectively.ConclusionTogether, our results provide novel molecular and cellular data towards understanding the immunological and hematological features of Roifman syndrome.

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