Journal of allergy and clinical immunology, 2017-10, Vol.140 (4), p.1112-1119
2017
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- Autor(en) / Beteiligte
- Titel
- Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations
- Ist Teil von
- Journal of allergy and clinical immunology, 2017-10, Vol.140 (4), p.1112-1119
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2017
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination. Its role in human immunity and hematopoiesis is poorly understood. We sought to investigate the clinical, cellular, and molecular features in 2 siblings presenting with progressive bone marrow failure (BMF), immunodeficiency, and developmental aberrations. We performed genome-wide homozygosity mapping, whole-exome and Sanger sequencing, immunophenotyping studies, and analysis of genotoxic stress responses. p38 activation, reactive oxygen species levels, rate of apoptosis and clonogenic survival, and growth in immune and nonimmune cells were assessed. The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) was monitored. We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts. Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1. MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased reactive oxygen species production, and decreased survival following UV light–induced DNA damage. Both patients were successfully treated with allogeneic HSCT with sustained reconstitution of hematopoietic defects. Here we show that MYSM1 deficiency is associated with developmental aberrations, progressive BMF with myelodysplastic features, and increased susceptibility to genotoxic stress. HSCT represents a curative therapy for patients with MYSM1 deficiency. [Display omitted]
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0091-6749eISSN: 1097-6825DOI: 10.1016/j.jaci.2016.10.053Titel-ID: cdi_proquest_miscellaneous_1861608618
- Format
- –
- Schlagworte
- Anemia, Apoptosis, Biopsy, Blood, Bone marrow, Bone Marrow Diseases - immunology, Cataracts, Cells, Cultured, Cognition, Consanguinity, Deoxyribonucleic acid, Developmental Disabilities - immunology, DNA, DNA damage, DNA Damage - immunology, DNA Repair - genetics, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Epigenetics, Gene mapping, Genome-Wide Association Study, Genomes, Genotoxicity, Genotype, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Histones - metabolism, Homozygosity, Humans, Immunodeficiency, Immunologic Deficiency Syndromes - immunology, Kinases, Leukocytes (granulocytic), Lymphocytes B, Mutation, Nonsense mutation, p38 Mitogen-Activated Protein Kinases - metabolism, p38 Protein, Patients, Pedigree, Penicillin, Phosphatase, Phosphorylation, Proteins, rare disease, Reactive oxygen species, Sequence Deletion - genetics, Siblings, Stem cell transplantation, Stem cells, Stop codon, Stress, Studies, Survival, Transcription, Transcription Factors - genetics, Transcription Factors - metabolism, Transplantation, Transplants & implants, Ubiquitination, Ultraviolet radiation