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Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):404-411
Hematopoiesis
A gain-of-function RAC2 mutation is associated with bone marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency
Chantal Lagresle-Peyrou,1,2,3 Aurélien Olichon,4 Hanem Sadek,3
Philippe Roche,5 Claudine Tardy,4 Cindy Da Silva,3 Alexandrine Garrigue,3 Alain Fischer,2,6,7 Despina Moshous,6 Yves Collette,5 Capucine Picard,2,6,8,9 Jean Laurent Casanova,2,6,10,11,12 Isabelle André1,2 and Marina Cavazzana1,2,3
1Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, F-75015 Paris, France; 2Paris Descartes University – Sorbonne Paris Cité, Imagine Institute UMR1163, F-75015 Paris, France; 3Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM CIC 1416, F-75015 Paris, France; 4Cancer Research Center of Toulouse, CRCT, University of Toulouse, UPS, INSERM U1037, F-31037 Toulouse, France; 5Marseille Cancer Research Center, CRCM, Aix Marseille University, Institut Paoli-Calmettes, CNRS, INSERM, Team ISCB, F-13273 Marseille, France; 6Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades University Hospital, APHP, F- 75015 Paris, France; 7College de France, F-75231 Paris, France; 8Study Center for Primary Immunodeficiencies, Assistance Publique–Hôpitaux de Paris (AP-HP), Necker- Enfants Malades University Hospital, F-75015 Paris, France; 9Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR 1163, Imagine Institute, F-75015 Paris, France; 10Laboratory of Human Genetics of Infectious Diseases, Necker Branch INSERM UMR 1163, Imagine Institute, F-75015 Paris, France; 11St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA and 12Howard Hughes Medical Institute, New York, NY, USA
ABSTRACT
Svere combined immunodeficiencies (SCID) 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.
Introduction
Severe combined immunodeficiencies (SCID) are inherited primary immunode- ficiencies characterized by a profound impairment of T-cell development and an intrinsic or functional defect in the B-cell compartment. Life-threatening SCID are the most severe primary immunodeficiencies; in the absence of treatment, SCID lead to death within the first year of life. The only curative treatments are allo- geneic hematopoietic stem cell transplantation (HSCT) or, for two types of SCID, autologous gene-modified HSCT.1 At present, all the SCID with a known molec- ular defect have an autosomal recessive pattern of inheritance or, in one case, X- linked inheritance. Less than 5% of SCID patients do not have a molecular diag- nosis.2,3
Reticular dysgenesis (RD) is the SCID form with the earlier clinical presentation (i.e., a few days after birth), due to the absence of both neutrophils and T cells. In
Correspondence:
MARINA CAVAZZANA
m.cavazzana@aphp.fr
CHANTAL LAGRESLE-PEYRO
chantal.lagresle@inserm.fr
Received: June 20, 2019. Accepted: January 8, 2020. Pre-published: January 9, 2020.
https://doi.org/10.3324/haematol.2019.230250
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