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

Amy P. Hsu*, Agnes Donkó, Megan E. Arrington, Muthulekha Swamydas, Danielle Fink, Arundhoti Das, Omar Escobedo, Vincent Bonagura, Paul Szabolcs, Harry N. Steinberg, Jenna Bergerson, Amanda Skoskiewicz, Melanie Mala Makhija, Joie Davis, Ladan Foruraghi, Cindy Palmer, Ramsay L Fuleihan, Joseph A. Church, Avinash Bhandoola, Michail S. LionakisSharon Campbell, Thomas L. Leto, Douglas B. Kuhns, Steven M. Holland

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1977-1988
Number of pages12
JournalBlood
Volume133
Issue number18
DOIs
StatePublished - May 2 2019

Fingerprint

Lymphopenia
Superoxides
Guanosine Triphosphate
Defects
Mutation
Neutrophils
Cells
Actins
Hydrolysis
B-Lymphocytes
p21-Activated Kinases
GTPase-Activating Proteins
Botulinum Toxins
Chemotaxis
Respiratory Tract Infections
NAD
Oxidoreductases
Phosphates
Membranes
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Hsu, A. P., Donkó, A., Arrington, M. E., Swamydas, M., Fink, D., Das, A., ... Holland, S. M. (2019). Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood, 133(18), 1977-1988. https://doi.org/10.1182/blood-2018-11-886028
Hsu, Amy P. ; Donkó, Agnes ; Arrington, Megan E. ; Swamydas, Muthulekha ; Fink, Danielle ; Das, Arundhoti ; Escobedo, Omar ; Bonagura, Vincent ; Szabolcs, Paul ; Steinberg, Harry N. ; Bergerson, Jenna ; Skoskiewicz, Amanda ; Makhija, Melanie Mala ; Davis, Joie ; Foruraghi, Ladan ; Palmer, Cindy ; Fuleihan, Ramsay L ; Church, Joseph A. ; Bhandoola, Avinash ; Lionakis, Michail S. ; Campbell, Sharon ; Leto, Thomas L. ; Kuhns, Douglas B. ; Holland, Steven M. / Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. In: Blood. 2019 ; Vol. 133, No. 18. pp. 1977-1988.
@article{62a54dad76df4714a4b05928c6297a70,
title = "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 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.",
author = "Hsu, {Amy P.} and Agnes Donk{\'o} and Arrington, {Megan E.} and Muthulekha Swamydas and Danielle Fink and Arundhoti Das and Omar Escobedo and Vincent Bonagura and Paul Szabolcs and Steinberg, {Harry N.} and Jenna Bergerson and Amanda Skoskiewicz and Makhija, {Melanie Mala} and Joie Davis and Ladan Foruraghi and Cindy Palmer and Fuleihan, {Ramsay L} and Church, {Joseph A.} and Avinash Bhandoola and Lionakis, {Michail S.} and Sharon Campbell and Leto, {Thomas L.} and Kuhns, {Douglas B.} and Holland, {Steven M.}",
year = "2019",
month = "5",
day = "2",
doi = "10.1182/blood-2018-11-886028",
language = "English (US)",
volume = "133",
pages = "1977--1988",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "18",

}

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, MM, Davis, J, Foruraghi, L, Palmer, C, Fuleihan, RL, Church, JA, Bhandoola, A, Lionakis, MS, Campbell, S, Leto, TL, Kuhns, DB & Holland, SM 2019, 'Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects', Blood, vol. 133, no. 18, pp. 1977-1988. https://doi.org/10.1182/blood-2018-11-886028

Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. / Hsu, Amy P.; Donkó, Agnes; Arrington, Megan E.; Swamydas, Muthulekha; Fink, Danielle; Das, Arundhoti; Escobedo, Omar; Bonagura, Vincent; Szabolcs, Paul; Steinberg, Harry N.; Bergerson, Jenna; Skoskiewicz, Amanda; Makhija, Melanie Mala; Davis, Joie; Foruraghi, Ladan; Palmer, Cindy; Fuleihan, Ramsay L; Church, Joseph A.; Bhandoola, Avinash; Lionakis, Michail S.; Campbell, Sharon; Leto, Thomas L.; Kuhns, Douglas B.; Holland, Steven M.

In: Blood, Vol. 133, No. 18, 02.05.2019, p. 1977-1988.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects

AU - Hsu, Amy P.

AU - Donkó, Agnes

AU - Arrington, Megan E.

AU - Swamydas, Muthulekha

AU - Fink, Danielle

AU - Das, Arundhoti

AU - Escobedo, Omar

AU - Bonagura, Vincent

AU - Szabolcs, Paul

AU - Steinberg, Harry N.

AU - Bergerson, Jenna

AU - Skoskiewicz, Amanda

AU - Makhija, Melanie Mala

AU - Davis, Joie

AU - Foruraghi, Ladan

AU - Palmer, Cindy

AU - Fuleihan, Ramsay L

AU - Church, Joseph A.

AU - Bhandoola, Avinash

AU - Lionakis, Michail S.

AU - Campbell, Sharon

AU - Leto, Thomas L.

AU - Kuhns, Douglas B.

AU - Holland, Steven M.

PY - 2019/5/2

Y1 - 2019/5/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065556444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065556444&partnerID=8YFLogxK

U2 - 10.1182/blood-2018-11-886028

DO - 10.1182/blood-2018-11-886028

M3 - Article

C2 - 30723080

AN - SCOPUS:85065556444

VL - 133

SP - 1977

EP - 1988

JO - Blood

JF - Blood

SN - 0006-4971

IS - 18

ER -

Hsu AP, Donkó A, Arrington ME, Swamydas M, Fink D, Das A et al. Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood. 2019 May 2;133(18):1977-1988. https://doi.org/10.1182/blood-2018-11-886028