title: Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Bahrami
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Witzel
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Racek
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Puchałka
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hollizeck
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Naschla
authors.initials: N
authors.lastname: Greif-Kohistani
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kotlarz
authors.affiliation: Institute for Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Core Facility Monoclonal Antibody Development, Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Feederle
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Roya
authors.initials: R
authors.lastname: Sherkat
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Steinemann
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelbeger
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, and Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany. Electronic address: christoph.klein@med.uni-muenchen.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D001855:Bone Marrow Diseases / Q000276:immunology*; D002478:Cells, Cultured; D003241:Consanguinity; D004249:DNA Damage / Q000276:immunology*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002658:Developmental Disabilities / Q000276:immunology*; D055106:Genome-Wide Association Study; D005838:Genotype; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006657:Histones / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D010375:Pedigree; D017384:Sequence Deletion / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C520745:MYSM1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D064570:Ubiquitin-Specific Proteases
keywords: Immunodeficiency; hematopoiesis; rare disease; stem cells; transplantation