MYSM1 deficiency - genotoxic stress-associated bone marrow failure and developmental aberrations

Publication date: Available online 21 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Ehsan Bahrami, Maximilian Witzel, Tomas Racek, Jacek Puchałka, Sebastian Hollizeck, Naschla Greif-Kohistani, Daniel Kotlarz, Hans-Peter Horny, Regina Feederle, Heinrich Schmidt, Roya Sherkat, Doris Steinemann, Gudrun Göhring, Brigitte Schlegelbeger, Michael H. Albert, Waleed Al-Herz, Christoph Klein
BackgroundMyb-Like, SWIRM and MPN domains 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination. Its role in human immunity and hematopoiesis is poorly understood.ObjectivesTo investigate the clinical, cellular and molecular features in two siblings presenting with progressive bone marrow failure, immunodeficiency and developmental aberrations.MethodsWe performed genome-wide homozygosity mapping, whole-exome sequencing (WES) and Sanger sequencing, immunophenotyping studies as well as analysis of genotoxic stress responses. p38 activation, reactive oxygen species (ROS), rate of apoptosis and clonogenic survival and growth in immune and non-immune cells were assessed. Outcome of allogeneic HSCT was monitored.ResultsWe report two patients with progressive bone marrow failure associated with myelodysplastic features, immunodeficiency affecting B-cells and neutrophil granulocytes, and complex developmental aberrations including mild skeletal anomalies, neurocognitive developmental delay, and cataracts. Whole exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding the histone deubiquitinase Myb-Like, SWIRM and MPN Domains 1 (MYSM1). MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased ROS production, and decreased survival upon UV light-induced DNA damage. Both patients were successfully treated using allogeneic hematopoietic stem cell transplantation (HSCT) with sustained reconstitution of hematopoietic defects.ConclusionsWe here show that MYSM1 deficiency is associated with developmental aberrations, progressive BMF with myelodysplastic features, and increased susceptibility to genotoxic stress. HSCT represent a curative therapy for patients with MYSM1 deficiency.

Graphical abstract

Teaser

MYSM1-deficiency causes a rare bone marrow failure syndrome


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