Irina Treise, head of the immunology screen of the German Mouse Clinic, has been awarded at the 29th International Mouse Genome Conference (08.-11.11.2015) with the
- Lorraine Flaherty Award in recognition of an outstanding oral presentation in the Trainee Symposium, and the
- award in recognition of an outstanding research poster
She presented the identification of a novel molecular pathomechanism of severe immunodeficiency.
As part of the large-scale Munich ENU (N-ethyl-N-nitrosourea) mouse mutagenesis approach, the Immunology Screen of the German Mouse Clinic performed standardized immuno-phenotyping of mouse mutants with a particular focus on identifying mutants with clinical phenotypes. Thereby, we established and characterized a novel mouse mutant - TUB006 - with defects in both innate and adaptive immunity. Heterozygous TUB006 animals show significantly reduced T cell frequencies, and fail to induce a sufficient T cell response to Listeria monocytogenes, resulting in lethality upon low-dose infection. Homozygous TUB006 mutants display an early lethal phenotype presenting with severe combined immunodeficiency (SCID) lacking all three major types of lymphocytes: T cells, B cells and NK cells. Furthermore, homozygous mutants develop sterile autoinflammation characterized by granulocytosis and infiltration of neutrophil granulocytes into various organs. Whole exome sequencing unraveled the underlying point mutation in Psmb10, encoding a catalytic subunit of the immunoproteasome and thymoproteasome. Yeast mutagenesis and crystallographic data suggest that the severe TUB006-phenotype is caused by structural changes that prevent the biogenesis of functional immuno- and thymoproteasomes. The severe immunodeficiency in TUB006 mice is surprising, since Psmb10-knockout mice are healthy, displaying only a subtly altered T cell repertoire. Our data once more show the power of ENU to identify unknown gene functions by creating not only loss-of-function mutants but also gain-of-function, hypo-/hypermorphs or dominant-negative mutations. The identification of causative mutations in mice with clinical phenotypes can directly lead to the discovery of human disease genes. Given the high structural and functional conservation of proteasome subunits between mammals, our data point out the high potential of Psmb10 mutations to be of clinical relevance in humans with immunological defects of unknown etiology.