An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation

Tangui Le Guen; Fabien Touzot; Isabelle André-Schmutz; Chantal Lagresle-Peyrou; Benoit France; Laetitia Kermasson; Nathalie Lambert; Capucine Picard; Patrick Nitschke; Wassila Carpentier; Christine Bole-Feysot; Annick Lim; Marina Cavazzana; Isabelle Callebaut; Jean Soulier; Nada Jabado; Alain Fischer; Jean-Pierre de Villartay; Patrick Revy

doi:10.1016/j.jaci.2015.06.008

An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation

J Allergy Clin Immunol. 2015 Dec;136(6):1619-1626.e5. doi: 10.1016/j.jaci.2015.06.008. Epub 2015 Jul 26.

Authors

Tangui Le Guen¹, Fabien Touzot², Isabelle André-Schmutz³, Chantal Lagresle-Peyrou⁴, Benoit France¹, Laetitia Kermasson¹, Nathalie Lambert⁵, Capucine Picard⁶, Patrick Nitschke⁷, Wassila Carpentier⁸, Christine Bole-Feysot⁹, Annick Lim¹⁰, Marina Cavazzana¹¹, Isabelle Callebaut¹², Jean Soulier¹³, Nada Jabado¹⁴, Alain Fischer³, Jean-Pierre de Villartay¹, Patrick Revy¹⁵

Affiliations

¹ INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Service de Bioinformatique, Faculté de Médecine Pitié Salpêtrière, Paris, France.
⁸ Plateforme Post-Génomique P3S, Faculté de Médecine Pitié Salpêtrière, Paris, France.
⁹ Plateforme de génomique, Institut Imagine, Paris, France.
¹⁰ Institut Pasteur, Groupe Immunoscope, Département d'Immunologie, Paris, France.
¹¹ Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Study Center of Primary Immunodeficiencies, AP-HP, Necker Hospital, Paris, France.
¹² CNRS UMR7590, Sorbonne Universités, Université Pierre et Marie Curie-Paris6-MNHN-IRD-IUC, Paris, France.
¹³ INSERM U944, Institut universitaire d'Hématologie, Université Denis Diderot, Paris, France.
¹⁴ McGill University and the Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
¹⁵ 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: [email protected].

PMID: 26220525
DOI: 10.1016/j.jaci.2015.06.008

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.

Objectives: 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.

Keywords: Hematopoiesis; MYSM1; genetic reversion; histone deubiquitinase; immunodeficiency.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

B-Lymphocytes / cytology
Cell Differentiation
DNA-Binding Proteins / genetics*
Hematopoiesis / genetics
Humans
Immunologic Deficiency Syndromes / genetics*
Infant
Lymphopenia / genetics
Male
Mutation
T-Lymphocytes / cytology
Trans-Activators
Transcription Factors / genetics*
Ubiquitin-Specific Proteases

Substances

DNA-Binding Proteins
MYSM1 protein, human
Trans-Activators
Transcription Factors
Ubiquitin-Specific Proteases