A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency

Chantal Lagresle-Peyrou (1) , Aurélien Olichon (2) , Hanem Sadek (1) , Philippe Roche (3) , Claudine Tardy (4) , Cindy da Silva , Alexandrine Garrigue (5) , Alain Fischer (5) , Despina Moshous (6) , Yves Collette (3) , Capucine Picard (7) , Jean Laurent Casanova (6) , Isabelle André (8, 6) , Marina Cavazzana (6)

1 Equipe Inserm U1163 - Human Lymphohematopoiesis Laboratory
2 LBCMCP - Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération
3 CRCM - Centre de Recherche en Cancérologie de Marseille
4 Régulations cellulaires: lipidoses et atherosclerose
5 Developpement Normal et Pathologique du Système Immunitaire
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 Inserm U980 - Génétique Humaine des Maladies Infectieuses
8 LISBP - Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés

Severe combined immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. They are defined by the absence of autologous T cells and the presence of an intrinsic or extrinsic defect in the B-cell compartment. In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R). This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter. Biochemical assays showed that the mutation was associated with a gain of function. The results of in vitro differentiation assays showed that RAC2 is essential for the survival and differentiation of hematopoietic stem/progenitor cells. Therefore, screening for RAC2 gain-of-function mutations should be considered in patients with a SCID phenotype and who lack a molecular diagnosis.

Mots clés: Immunodeficiencies; Leukemic Stem Cell; Hematopoietic Stem Cell; Bone Marrow Failure; Hematopoiesis

Domaines: Hématologie; Biologie cellulaire; Immunologie; Génétique humaine

Chantal Lagresle-Peyrou, Aurélien Olichon, Hanem Sadek, Philippe Roche, Claudine Tardy, et al.. A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency. Haematologica, inPress, ⟨10.3324/haematol.2019.230250⟩. ⟨hal-02545998⟩