A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease

Smits, Bas M.; Lelieveld, P.H.C.; Ververs, Francesca A.; Turkenburg, Marjolein; Koning, Coco de; Dijk, Marc van; Leavis, Helen L.; Boelens, Jaap Jan; Lindemans, Caroline A.; Bloem, Andries C.; Corput, Lisette van de; Montfrans, Joris van; Nierkens, Stefan; Gijn, Mariëlle van; Geerke, Daan P.; Waterham, Hans R.; Koenderman, Leo; Boes, Marianne

doi:10.1016/j.clim.2019.108248

Cited by 20 publications

(17 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5. Similar to STAT1 [40], variants in RAC2 [41][42][43][44][45] or CARD11 [25,26,28] can be pathogenic either as monoallelic GOF or LOF or bi-allelic recessive LOF.…”

Section: A Heterozygous Hypermorphic Variant In Ikbkb Wasmentioning

confidence: 99%

“…: 50 Total number of mutant genes:58 New inborn errors of immunity: 8; New inborn errors of immunity: 8; RAC2 GOF[42][43][44][45]; ICOSLG[53]; AD DN IKZF1[38]; POLD1[54,55]; POLD2[54]; RELA[56,57]; REL[58]; FCHO1[59] SCID severe combined immunodeficiency, CID combined immunodeficiency, EBV Epstein-Barr virus, MHC major histocompatibility complex, HPV human papillomavirus, Treg T regulatory cell, XL Xlinked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function…”

mentioning

confidence: 99%

See 1 more Smart Citation

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

et al. 2020

View full text Add to dashboard Cite

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

show abstract

“…5. Similar to STAT1 [40], variants in RAC2 [41][42][43][44][45] or CARD11 [25,26,28] can be pathogenic either as monoallelic GOF or LOF or bi-allelic recessive LOF.…”

Section: A Heterozygous Hypermorphic Variant In Ikbkb Wasmentioning

confidence: 99%

mentioning

confidence: 99%

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Examples of genes displaying such allelic series include CARD11, consisting of heterozygous mutations that cause distinct phenotypes through negative dominance (hyper IgE syndrome) or hypermorphism (B cell expansion with NF-kB and T cell anergy), whereas biallelic mutations lead to LoF ((severe) combined immunodeficiency) [20]. Moreover, both hypermorphic and LoF mutations in STAT1 [21,22] and RAC2 [23,24] cause distinct forms of PID. These examples illustrate the presence of allelic series and add to the complexity of genotypephenotype relationships, which complicates correct variant interpretation using NGS.…”

Section: Genetics Of Pidsmentioning

confidence: 99%

Next-Generation Sequencing in the Field of Primary Immunodeficiencies: Current Yield, Challenges, and Future Perspectives

Vorsteveld

Hoischen

Made

2021

Clinic Rev Allerg Immunol

View full text Add to dashboard Cite

Primary immunodeficiencies comprise a group of inborn errors of immunity that display significant clinical and genetic heterogeneity. Next-generation sequencing techniques and predominantly whole exome sequencing have revolutionized the understanding of the genetic and molecular basis of genetic diseases, thereby also leading to a sharp increase in the discovery of new genes associated with primary immunodeficiencies. In this review, we discuss the current diagnostic yield of this generic diagnostic approach by evaluating the studies that have employed next-generation sequencing techniques in cohorts of patients with primary immunodeficiencies. The average diagnostic yield for primary immunodeficiencies is determined to be 29% (range 10–79%) and 38% specifically for whole-exome sequencing (range 15–70%). The significant variation between studies is mainly the result of differences in clinical characteristics of the studied cohorts but is also influenced by varying sequencing approaches and (in silico) gene panel selection. We further discuss other factors contributing to the relatively low yield, including the inherent limitations of whole-exome sequencing, challenges in the interpretation of novel candidate genetic variants, and promises of exploring the non-coding part of the genome. We propose strategies to improve the diagnostic yield leading the way towards expanded personalized treatment in PIDs.

show abstract

“…Since 2019, several groups have reported germline monoallelic activating gain-of-function mutations in RAC2, including p.G12R, p.P34H, p.Q61R, p.E62K, and p.N92T. These hyperactivating mutations resulted in combined immunode ciency (CID) or severe combined immunode ciency (SCID) phenotypes, associated with severe lymphopenia, recurrent sinopulmonary infections, and invasive viral infections, or severe bone marrow hypoplasia and absence of circulating leukocytes [19][20][21][22][23][24], providing crucial insights into the roles of RAC2 in human leukocyte biology and helping to elucidate the signi cance of RAC2 modi cation.…”

Section: Introductionmentioning

confidence: 99%

Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation

Zhao

Zhang

Chen

et al. 2022

Preprint

View full text Add to dashboard Cite

Ras-related C3 botulinum toxin substrate 2 (RAC2) is a GTPase exclusively expressed in hematopoietic cells, that acts as a pivotal regulator of several aspects of cell behavior via various cellular processes. RAC2 undergoes a tightly-regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch. Mutations in RAC2 have been identified in 18 patients with different forms of primary immunodeficiency, ranging from phagocyte defects caused by dominant negative mutations to common variable immunodeficiency resulting from autosomal recessive loss-of-function mutations, or severe combined immunodeficiency due to dominant activating gain-of-function mutations. Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis. Immunological investigations revealed low T-cell receptor extension circle/K-deleting recombination excision circles numbers, lymphopenia, and low serum immunoglobulin G. Targeted next generation sequencing identified a novel heterozygous mutation in RAC2, c.86C>G (p.P29R), located in the highly-conserved Switch I domain. The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes. Further, the dominant activating RAC2 mutation led to accelerated apoptosis with augmented intracellular active caspase 3, impaired actin polarization in lymphocytes and neutrophils, and diminished RAC2 polarization in neutrophils. We present a novel RAC2 gain-of-function mutation with implications for immunodeficiency and linked to functional dysregulation, including abnormal apoptosis and cell polarization arising from altered RAC2 expression. Thus, our findings broaden the spectrum of known RAC2 mutations and their underlying mechanisms.

show abstract

A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease

Cited by 20 publications

References 10 publications

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

Next-Generation Sequencing in the Field of Primary Immunodeficiencies: Current Yield, Challenges, and Future Perspectives

Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation

Contact Info

Product

Resources

About