Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome
| Autor: | Kathleen Stirrups, Chris Van Geet, Stephanie Humblet-Baron, Ernest Turro, Daniel Greene, Isabelle Meyts, Erika Van Nieuwenhove, Roxanne Collin, Patrick Matthys, Karen Put, Sylvie Lesage, Jessica Heremans, Adrian Liston, Josselyn E. Garcia-Perez, Christopher J. Penkett, Ingele Casteels, Francis de Zegher, Chantal Thys, Kathleen Freson, Susan M. Schlenner, Carine Wouters |
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| Rok vydání: | 2018 |
| Předmět: |
Blood Platelets
0301 basic medicine Adolescent Primary Immunodeficiency Diseases Megakaryocyte differentiation Immunology Biology Osteochondrodysplasias Compound heterozygosity 03 medical and health sciences Retinal Diseases Megakaryocyte RNA Small Nuclear Exome Sequencing medicine Humans Protein Splicing Immunology and Allergy Cell Lineage Child MAPK1 Cells Cultured Thrombopoietin Cell Proliferation Mitogen-Activated Protein Kinase 1 B-Lymphocytes Precursor Cells B-Lymphoid Immunologic Deficiency Syndromes Intron Infant Cell Differentiation Pedigree 030104 developmental biology medicine.anatomical_structure Child Preschool RNA splicing Mental Retardation X-Linked Cancer research Dense granule Cardiomyopathies Megakaryocytes Signal Transduction |
| Zdroj: | Journal of Allergy and Clinical Immunology. 142:630-646 |
| ISSN: | 0091-6749 |
| DOI: | 10.1016/j.jaci.2017.11.061 |
| Popis: | 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. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:142 issue:2 pages:630-646 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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