Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects.

Abstract:

:Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 phox , 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.

journal_name

Blood

journal_title

Blood

authors

Hsu AP,Donkó A,Arrington ME,Swamydas M,Fink D,Das A,Escobedo O,Bonagura V,Szabolcs P,Steinberg HN,Bergerson J,Skoskiewicz A,Makhija M,Davis J,Foruraghi L,Palmer C,Fuleihan RL,Church JA,Bhandoola A,Lionakis MS,Camp

doi

10.1182/blood-2018-11-886028

subject

Has Abstract

pub_date

2019-05-02 00:00:00

pages

1977-1988

issue

18

eissn

0006-4971

issn

1528-0020

pii

blood-2018-11-886028

journal_volume

133

pub_type

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