Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections

Sharapova, Svetlana O.; Haapaniemi, Emma; Sakovich, Inga; Kostyuchenko, Larysa; Donkó, Ágnes; Dulau‐Florea, Alina; Malko, Oksana; Bondarenko, Anastasia V.; Stegantseva, Maria; Leto, Thomas L.; Uygun, Vedat; Karasu, Gülsün; Holland, Steven M.; Hsu, Amy P.; Алейникова, О. В.

doi:10.1016/j.clim.2019.05.003

Cited by 31 publications

(28 citation statements)

References 10 publications

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“…A similar phenotype was described by Sharapova et al 43 . The female patient, born to nonconsanguineous parents, presented with lymphopenia, low TRECs and kappa‐deleting recombinant excision circles (KRECs), hypogammaglobulinemia, and low memory B cells.…”

Section: Introductionsupporting

confidence: 72%

“…The P34H, E62K, and N92T monoallelic mutations in RAC2 have been shown to have an activating effect; these variants are associated with severe lymphopenia, viral infections, and invasive infections, resembling a CID 41‐43 . The activating effect of these mutations leads to a hyperactive state of patients’ neutrophils upon fMLP stimulation, in clear contrast with what observed in the case of the dominant negative RAC2 mutation.…”

Section: Discussionmentioning

confidence: 96%

“…Recently, three different groups reported germline monoallelic activating mutations in RAC2, all resulting in a combined immunodeficiency (CID) phenotype 41‐43 …”

Section: Introductionmentioning

confidence: 99%

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RAC2 and primary human immune deficiencies

Lougaris

Baronio

Gazzurelli

et al. 2020

Journal of Leukocyte Biology

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RAC2 is a GTPase that is exclusively expressed in hematopoietic cells. Animal models have suggested important roles for RAC2 in the biology of different cell types, such as neutrophils and lymphocytes. Primary immunodeficiencies represent "experimentum naturae" and offer priceless insight on the function of the human immune system. Mutations in RAC2 have been identified in a small number of patients giving rise to different forms of primary immunodeficiencies ranging from granulocyte defects caused by dominant negative mutations to combined immunodeficiency due to dominant activating mutations. This review will focus on the clinical and immunologic phenotype of patients with germline mutations in RAC2.

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Section: Introductionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 96%

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RAC2 and primary human immune deficiencies

Lougaris

Baronio

Gazzurelli

et al. 2020

Journal of Leukocyte Biology

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“…Rare AR subgroups (<5% of CGD cases) are caused by mutations in CYBA, NCF2 or NCF4 genes encoding p22 phox , p67 phox , or p40 phox subunits, respectively (8)(9)(10). In very rare cases, the small G protein, Rac2, involved in regulating NADPH oxidase activity could also be mutated leading to a specific innate immunodeficiency characterized by an unresponsiveness to the chemotactic peptide FormylMetLeuPhe (for NADPH oxidase activity and chemotaxis) (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Second Report of Chronic Granulomatous Disease in Jordan: Clinical and Genetic Description of 31 Patients From 21 Different Families, Including Families From Lybia and Iraq

et al. 2021

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Chronic granulomatous Disease (CGD) is a rare innate immunodeficiency disorder caused by mutations in one of the six genes (CYBA, CYBB, NCF1, NCF2, NCF4, and CYBC1/EROS) encoding the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH)—oxidase complex in phagocytes. In the Western population, the most prevalent form of CGD (about two-thirds of all cases) is the X-linked form (X-CGD) caused by mutations in CYBB. The autosomal recessive forms (AR-CGD), due to mutations in the other genes, collectively account for the remaining one-third of CGD cases. We investigated the clinical and molecular features of 22 Jordanian, 7 Libyan, and 2 Iraqi CGD patients from 21 different families. In addition, 11 sibling patients from these families were suspected to have been died from CGD as suggested by their familial and clinical history. All patients except 9 were children of consanguineous parents. Most of the patients suffered from AR-CGD, with mutations in CYBA, NCF1, and NCF2, encoding p22phox, p47phox, and p67phox proteins, respectively. AR-CGD was the most frequent form, in Jordan probably because consanguineous marriages are common in this country. Only one patient from non-consanguineous parents suffered from an X910 CGD subtype (0 indicates no protein expression). AR670 CGD and AR220 CGD appeared to be the most frequently found sub-types but also the most severe clinical forms compared to AR470 CGD. As a geographical clustering of 11 patients from eight Jordanian families exhibited the c.1171_1175delAAGCT mutation in NCF2, segregation analysis with nine polymorphic markers overlapping NCF2 indicates that a common ancestor has arisen ~1,075 years ago.

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“…Recently it was demonstrated that mutations in EROS/CYBC1 are responsible for a decrease in NADPH oxidase activity of phagocytes, leading to chronic granulomatous disease [8]. A small G protein, Rac2, is also involved in regulating NADPH oxidase activity and can be mutated in rare cases, leading to an innate immunodeficiency [9–15]. In resting cells, membrane and cytosolic components of the NADPH oxidase complex are dissociated, while in stimulated phagocytes they become associated at the membrane, leading to an active oxidase complex able to produce superoxide anions [16].…”

Section: Introductionmentioning

confidence: 99%

Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants – identification of 11 novel mutations inCYBB

Mollin

Beaumel

Vigne

et al. 2020

Clinical and Experimental Immunology

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Summary Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910, X91− or X91+), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910-CGD and two X91−-CGD). One X910-CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91−-CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91−-CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91−-CGD patients correlates with mild clinical forms of CGD, whereas X910-CGD and X91+-CGD cases remain the most clinically severe forms.

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Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections

Cited by 31 publications

References 10 publications

RAC2 and primary human immune deficiencies

RAC2 and primary human immune deficiencies

Second Report of Chronic Granulomatous Disease in Jordan: Clinical and Genetic Description of 31 Patients From 21 Different Families, Including Families From Lybia and Iraq

Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants – identification of 11 novel mutations inCYBB

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