title: An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.
abstract: BACKGROUND
  Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities.
  
  
  OBJECTIVE
  We sought to characterize the underlying genetic cause of this syndrome.
  
  
  METHODS
  We performed genome-wide homozygosity mapping, followed by whole-exome sequencing.
  
  
  RESULTS
  Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell.
  
  
  CONCLUSIONS
  We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.
authors.affiliation: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Tangui
authors.initials: T
authors.lastname: Le Guen
authors.affiliation: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: André-Schmutz
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; CIC-BT 502 INSERM, Paris, France, and Département de Biothérapie, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Lagresle-Peyrou
authors.affiliation: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: France
authors.affiliation: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Kermasson
authors.affiliation: AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France; Study Center of Primary Immunodeficiencies, AP-HP, Necker Hospital, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France; Study Center of Primary Immunodeficiencies, AP-HP, Necker Hospital, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Service de Bioinformatique, Faculté de Médecine Pitié Salpêtrière, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: Plateforme Post-Génomique P3S, Faculté de Médecine Pitié Salpêtrière, Paris, France.
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.affiliation: Plateforme de génomique, Institut Imagine, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Institut Pasteur, Groupe Immunoscope, Département d'Immunologie, Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Study Center of Primary Immunodeficiencies, AP-HP, Necker Hospital, Paris, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.affiliation: CNRS UMR7590, Sorbonne Universités, Université Pierre et Marie Curie-Paris6-MNHN-IRD-IUC, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.affiliation: INSERM U944, Institut universitaire d'Hématologie, Université Denis Diderot, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: McGill University and the Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; AP-HP, Hôpital Necker Enfants-Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.affiliation: INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address: patrick.revy@inserm.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D008231:Lymphopenia / Q000235:genetics; D008297:Male; D009154:Mutation; D013601:T-Lymphocytes / Q000166:cytology; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D064570:Ubiquitin-Specific Proteases
chemical_list: D004268:DNA-Binding Proteins; C520745:MYSM1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D064570:Ubiquitin-Specific Proteases
keywords: Hematopoiesis; MYSM1; genetic reversion; histone deubiquitinase; immunodeficiency