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