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Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects
- Source :
- Blood
- Publication Year :
- 2019
- Publisher :
- American Society of Hematology, 2019.
-
Abstract
- Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67phox, activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)–bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.
- Subjects :
- Adult
0301 basic medicine
Immunobiology and Immunotherapy
Adolescent
GTP'
Membrane ruffling
Immunology
RAC1
GTPase
Guanosine triphosphate
Biochemistry
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Lymphopenia
Animals
Humans
Cytoskeleton
Chemistry
Superoxide
Kinase
Immunologic Deficiency Syndromes
Infant, Newborn
Infant
Actin remodeling
Cell Biology
Hematology
Molecular biology
Pedigree
rac GTP-Binding Proteins
Mice, Inbred C57BL
030104 developmental biology
Child, Preschool
Gain of Function Mutation
Female
030215 immunology
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 133
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....64f592786f89f797b302b94253065af0