An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation - 04/12/15
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.
Le texte complet de cet article est disponible en PDF.Key words : Hematopoiesis, immunodeficiency, MYSM1, genetic reversion, histone deubiquitinase
Abbreviations used : APC, H2A, HSC, JAMM, KO, MYSM1, NK, PE, WGHM, WT
Plan
| Supported by institutional grants from INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée La Ligue), GIS-Institut des maladies rares, ARC, INCa/Cancéropôle Ile de France, Institut Imagine, and the European Research Council (PIDIMMUN grant no. 249816). This program has received a state subsidy managed by the National Research Agency under the “Investments for the Future” program bearing the reference ANR-10-IAHU-01. T.L.G received fellowships from La Ligue contre le cancer, and B.F. received fellowships from Canceropôle. P.R. is a scientist from Centre National de la Recherche Scientifique (CNRS). |
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| Disclosure of potential conflict of interest: P. Revy received research support from ARC, La Ligue, INCa, ANR, GIS-Institut des European Research Council. The rest of the other authors declare that they have no relevant conflicts of interest. |
Vol 136 - N° 6
P. 1619 - décembre 2015 Retour au numéro
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