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An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation
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International audience. Myb-Like, SWIRM, and MPN domains 1(MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatinmarker associated with gene transcription silencing. Likewise, ithas been reported that murine Mysm1 participates intranscription derepression of genes, among which aretranscription factors involved in hematopoietic stem cellhomeostasis, hematopoiesis, and lymphocyte differentiation.However, whether MYSM1 has a similar function in humansubjects remains unclear. Here we describe a patient presentingwith a complete lack of B lymphocytes, T-cell lymphopenia,defective hematopoiesis, and developmental abnormalities.Objectives: We sought to characterize the underlying geneticcause of this syndrome.Methods: We performed genome-wide homozygosity mapping,followed by whole-exome sequencing.Results: Genetic analysis revealed that this novel disorder iscaused by a homozygous MYSM1 missense mutation affectingthe catalytic site within the deubiquitinase JAB1/MPN/Mov34(JAMM)/MPN domain. Remarkably, during the course of ourstudy, the patient recovered a normal immunohematologicphenotype. Genetic analysis indicated that this improvementoriginated from a spontaneous genetic reversion of the MYSM1mutation in a hematopoietic stem cell.Conclusions: We here define a novel human immunodeficiencyand provide evidence that MYSM1 is essential for properimmunohematopoietic development in human subjects. Inaddition, we describe one of the few examples of spontaneousin vivo genetic cure of a human immunodeficiency.
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