Chantal Lagresle-Peyrou, France
Inserm. Institut Imagine CIC biotherapiePresenter of 1 Presentation
A GAIN-OF-FUNCTION RAC2 MUTATION IS ASSOCIATED WITH BONE-MARROW HYPOPLASIA AND AN AUTOSOMAL DOMINANT FORM OF SEVERE COMBINED IMMUNODEFICIENCY
Abstract
Background and Aims
Severe combined immunodeficiencies (SCIDs) form a heterogeneous group of life-threatening genetic disorders defined by the absence of autologous T cells and an intrinsic or extrinsic defect in the B-cell compartment. We studied three newborn patients with clinical and biological features of SCID associated with bone-marrow hypoplasia and unknown molecular diagnosis. Given the severity of the clinical presentation, the patients had to undergo allogenic hematopoietic stem cell transplantation in the first weeks of life.
Methods
Whole-genome sequencing (WES), biochemical analyses and in vitro cultures were performed in order to characterize the molecular defect.
Results
In the three patients we identified the same heterozygous, dominant missense mutation in the RAC2 gene . The mutation, located in the GDP/GTP binding pocket of the RAC2 GTPase protein (p.G12R), is associated with a gain of function. The results of in vitro differentiation assays highlighted that RAC2 signalling pathway has a key function in regulating the survival and differentiation of hematopoietic stem/progenitor cells toward lymphoid and myeloid lineages.
Conclusions
The present study is the first to report an autosomal dominant form of SCID and suggest that RAC2 gene sequencing should be considered for patients with SCID clinical presentation.