Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations

(2017) Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations. Journal of Allergy and Clinical Immunology. pp. 1112-1119. ISSN 0091-6749

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Abstract

Background: 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. Objectives: We sought to investigate the clinical, cellular, and molecular features in 2 siblings presenting with progressive bone marrow failure (BMF), immunodeficiency, and developmental aberrations. Methods: 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. Results: 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. Conclusions: 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.

Item Type: Article
Keywords: immunodeficiency stem cells hematopoiesis rare disease transplantation histone h2a deubiquitinase stem-cell maintenance double-strand breaks lymphocyte differentiation epigenetic regulation reference values uv-radiation p53 protein hematopoiesis phosphorylation
Divisions: Acquired Immunodeficiency Research Center
Page Range: pp. 1112-1119
Journal or Publication Title: Journal of Allergy and Clinical Immunology
Journal Index: ISI
Volume: 140
Number: 4
Identification Number: https://doi.org/10.1016/j.jaci.2016.10.053
ISSN: 0091-6749
Depositing User: مهندس مهدی شریفی
URI: http://eprints.mui.ac.ir/id/eprint/262

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