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

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

  • J Allergy Clin Immunol. 2017 Oct;140(4):1112-1119. doi: 10.1016/j.jaci.2016.10.053.
Ehsan Bahrami 1,  Maximilian Witzel 1,  Tomas Racek 1,  Jacek Puchałka 1,  Sebastian Hollizeck 1,  Naschla Greif-Kohistani 1,  Daniel Kotlarz 1,  Hans-Peter Horny 2,  Regina Feederle 3,  Heinrich Schmidt 1,  Roya Sherkat 4,  Doris Steinemann 5,  Gudrun Göhring 5,  Brigitte Schlegelbeger 5,  Michael H Albert 1,  Waleed Al-Herz 6,  Christoph Klein 7
Affiliations

Affiliations

  • 1 Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
  • 2 Institute for Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
  • 3 Helmholtz Zentrum München, German Research Center for Environmental Health, Core Facility Monoclonal Antibody Development, Munich, Germany.
  • 4 Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
  • 5 Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
  • 6 Department of Pediatrics, Faculty of Medicine, Kuwait University, and Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait.
  • 7 Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany. Electronic address: [email protected].
PMID: 28115216 DOI: 10.1016/j.jaci.2016.10.053
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.

Keywords

Immunodeficiency; hematopoiesis; rare disease; stem cells; transplantation.

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