Table 1.

List of actinopathies with corresponding protein function, clinical symptoms, and neutrophil defects

Disease	Protein function	Clinical symptoms	Defects reported in primary neutrophils from patients
ACTB mutations	Non-muscle actin isoform	Recurrent infections and mental disability	Impaired chemotaxis and ROS production, lower membrane potential response
MKL1 deficiency	Co-activator of SRF	Severe, recurrent bacterial infections	Reduced actin content and impaired actin polymerization, impaired migration, impaired spreading, enhanced degranulation, and defective endothelial transmigration
ARPC1B deficiency	Component of the ARP2/3 complex	Viral and bacterial infections, bleeding tendency, vasculitis, eczema, allergy, thrombocytopenia, and eosinophilia	Impaired actin polymerization, impaired motility, enhanced degranulation, and impaired podosome formation
Wiskott-Aldrich syndrome (WAS)	Nucleation factor for the ARP2/3 complex	Recurrent infections, severe bleeding, eczema, autoimmune diseases, lymphoma, thrombocytopenia, and lymphocytopenia	None reported
X-linked thrombocytopenia (WAS)	Nucleation factor for the ARP2/3 complex	Mild immunodeficiency, bleeding, and thrombocytopenia	None reported
X-linked neutropenia (WAS)	Nucleation factor for the ARP2/3 complex	Severe neutropenia, monocytopenia, thrombocytopenia, late-onset malignancies, and recurrent infections	Enhanced basal F-actin levels, proliferation, and maturation defect
WIP deficiency (WIPF1)	Interactor of WASP and keeps WASP stable and inactive	Recurrent infections, eczema, papulovesicular/ulcerative lesions, bloody diarrhea, and thrombocytopenia	None reported
HEM1 deficiency	Component of the WRC	Recurrent bacterial and viral infections and atopic and allergic disease	Impaired migration
Coronin-1A deficiency	Actin-binding protein, interacts with the ARP2/3 complex, signaling mediator	Recurrent bacterial and viral respiratory infections, skin lesions, chronic warts, and chronic T-lymphopenia	Very short telomere length
LLS/WDR1 deficiency	Enhances severing and disassembly of actin filaments by cofilin	Severe stomatitis, recurrent infections and moderate neutropenia (periodic), fever, thrombocytopenia, and intellectual impairment	Migration defect, abnormal spreading, increased basal F-actin levels, enhanced ROS production, and abnormal location of the nucleus
RAC2 mutations (activating)	Rho GTPase involved in the respiratory burst and activator of the WRC	Neutropenia, recurrent respiratory infections, and lymphopenia	Impaired chemotaxis, increased basal F-actin levels, increased actin polymerization, and increased ROS production
RAC2 mutations (loss-of-function)	Rho GTPase involved in the respiratory burst and activator of the WRC	Neutrophilia, severe bacterial infections, poor wound-healing, lymphopenia, and hypogammaglobulinemia	Impaired chemotactic response, decreased basal F-actin levels, impaired actin polymerization, decreased ROS production, and absent azurophilic granule release
DOCK2 deficiency	GEF activating RAC	Severe bacterial and viral infections and T-cell lymphopenia	Impaired actin polymerization and impaired ROS production
DOCK8 deficiency	GEF activating CDC42	Severe recurrent viral, bacterial, and fungal infections; eczema; and allergies	Mild motility defect
STK4 deficiency	Kinase for several nuclear proteins and activator of RAC through PKC-α and LyGDI	Recurrent bacterial and viral infections, CD4+ T-lymphopenia, mucocutaneous candidiasis, eczema, molluscum contagiosum, high IgA/E levels, cardiac aberrations, and episodes of neutropenia	Loss of mitochondrial membrane potential and susceptibility to apoptosis
MSN deficiency	Links actin filaments to the plasma membrane and signaling mediator for selectins	Recurrent bacterial and viral infections, recurrent molluscum, eczema, and lymphopenia	None reported
LAD-I (ITGB2)	Facilitates cell-cell and cell-ECM interactions	Early onset recurrent bacterial or fungal infections, delayed umbilical cord detachment, omphalitis, poor wound healing, non-pyogenic wounds, and severe neutrophilia	Impaired ROS production, reduced killing of Candida albicans, impaired adhesion (static and flow), defective chemotaxis, and defective endothelial transmigration
LAD-III (FERMT3)	Key-activator of integrins	Milder immune deficiency compared to LAD-I, but accompanied by a Glanzmann-like bleeding disorder	Impaired ROS production, reduced killing of C. albicans, impaired adhesion (static and flow), defective chemotaxis, and defective endothelial transmigration
CalDAG-GEFI deficiency	GEF activating RAP1	Impaired platelet function and bleeding disorder	Defective integrin activation
NAD	Unknown gene	Recurrent fevers, recurrent pulmonary infections, leukocytosis, non-pyogenic infections, hepatosplenomegaly, and thrombocytopenia	Decreased basal F-actin levels, impaired actin polymerization, impaired podosome formation, and increased ROS production

ACTB, β-actin; ARPC1B, actin-related protein complex 2/3 subunit 1B; ARP2/3 complex, actin-related protein complex 2/3; CalDAG-GEFI, calcium and DAG-regulated guanine nucleotide exchange factor I; CD, marker of cell differentiation; CDC42, cell division control protein 42; DOCK, dedicator of cytokinesis; ECM, extracellular matrix; FERMT3, fermitin family homolog 3; F-actin, filamentous actin; GEF, guanidine exchange factor; Ig, immunoglobin; ITGB2, β-2-integrin; LAD, leukocyte adhesion deficiency; LLS, lazy leukocyte syndrome; LyGDI, lysine GDP-dissociation inhibitor; MKL1, megakaryoblastic leukemia 1; MSN, moesin; NAD, neutrophil actin dysfunction; PKC, protein kinase C; RAC, Ras-related C3 botulinum toxin substrate; RAP1, Ras-related protein 1; Rho GTPase, rho guanidine triphosphosphatase; ROS, reactive oxygen species; SRF, serum response factor; STK4, serine/threonine kinase 4; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich syndrome protein; WAVE, WASP family verprolin-homologous protein; WRC, WAVE regulatory complex; WDR1, WD repeat-containing domain 1; WIP, WASP-interacting protein.