Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome - 04/08/18
National Institute for Health Research BioResource
Chantal Thys, BSc a, Chris Van Geet, MD, PhD a, j, Erika Van Nieuwenhove, MD b, c, j, Carine Wouters, MD, PhD c, j, ‡ , Isabelle Meyts, MD, PhD c, j, ‡ , Kathleen Freson, PhD a, ⁎, ‡ , Adrian Liston, PhD b, c, ⁎, ‡Abstract |
Background |
Roifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia, and, in some patients, thrombocytopenia. Compound heterozygous variants in the small nuclear RNA gene RNU4ATAC, which is necessary for U12-type intron splicing, were identified recently as driving Roifman syndrome.
Objective |
We studied 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC to gain insight into the mechanisms behind this disorder.
Methods |
We systematically profiled the immunologic and hematologic compartments of the 3 patients with Roifman syndrome and performed RNA sequencing to unravel important splicing defects in both cell lineages.
Results |
The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. Despite abundant B-cell activating factor availability, development past this B-cell activating factor–dependent stage was crippled, with disturbed minor splicing of the critical mitogen-activated protein kinase 1 signaling component. In the hematologic compartment patients with Roifman syndrome demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Platelets from patients with Roifman syndrome were rounder, with increased tubulin and actin levels, and contained increased α-granule 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.
Conclusion |
Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : B cells, platelets, RNA processing, Roifman syndrome
Abbreviations used : APRIL, BAFF, BAFF-R, BCR, BeviMed, BLOC3, EM, HSC, ITP, MAPK1, MK, MOPD1, MPV, NK, PRP, RNAseq, snRNA, vWF
Plan
Supported by the National Institute for Health Research of England (award no. RG65966 to NIHR BioResource–Rare Diseases), Research Foundation–Flanders (grant no. 1S00816N to J.H., 1272517N to S.H.-B., 1S22716N to E.V.N., and G.0B17.13N to K.F.), the Research Council of the University of Leuven (BOF KU Leuven, OT/14/098 to K.F.), and the ERC (Immuno ERC-2010-StG_20091118 to A.L.). C.V.G. is holder of the Bayer and Norbert Heimburger (CSL Behring) Chairs. |
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Disclosure of potential conflict of interest: J. Heremans has received personal fees from Research Foundation–Flanders (1S00816N). S. Humblet-Baron has received personal fees from Research Foundation–Flanders (1272517N). E. Van Nieuwenhove has received personal fees from Research Foundation–Flanders (1S22716N). C. Wouters has received a grant from GlaxoSmithKline. I. Meyts has received grants from CSL Behring and the JM Foundation. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 2
P. 630-646 - août 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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