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

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...

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Bibliographic Details
Published in:Haematologica (Roma) 2021-02, Vol.106 (2), p.404-411
Main Authors: Lagresle-Peyrou, Chantal, Olichon, Aurélien, Sadek, Hanem, Roche, Philippe, Tardy, Claudine, Da Silva, Cindy, Garrigue, Alexandrine, Fischer, Alain, Moshous, Despina, Collette, Yves, Picard, Capucine, Casanova, Jean Laurent, André, Isabelle, Cavazzana, Marina
Format: Article
Language:English
Subjects:
Bone Marrow
Bone Marrow Failure Disorders
Cellular Biology
Female
Gain of Function Mutation
Genetics
Hematology
Hematopoietic Stem Cell Transplantation
Human genetics
Human health and pathology
Humans
Immunology
Infant, Newborn
Life Sciences
Mutation
rac GTP-Binding Proteins
RAC2 GTP-Binding Protein
Severe Combined Immunodeficiency - diagnosis
Severe Combined Immunodeficiency - genetics
Severe Combined Immunodeficiency - therapy
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Summary: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.
ISSN:0390-6078
1592-8721
DOI:10.3324/haematol.2019.230250