Systemic Inflammation and Myelofibrosis in a Patient with
Takenouchi-Kosaki Syndrome due to CDC42 Tyr64Cys
Mutation

Bucciol, Giorgia; Pillay, Bethany; Casas-Martín, José; Delafontaine, Selket; Proesmans, Marijke; Lorent, Natalie; Coolen, Johan; Tousseyn, Thomas; Bossuyt, Xavier; Cindy, S.; Schrijvers, R.; Tangye, Stuart G.; Moens, Leen; Meyts, Isabelle

doi:10.1007/s10875-020-00742-5

Cited by 33 publications

(29 citation statements)

References 12 publications

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“…Impaired lymphocyte activation in actinopathies reduces the ability to fight viral infections, and HLH observed in these disorders is frequently triggered by viral, particularly EBV, infection. The fact that no viral trigger for HLH was detected in our patients does not fully exclude that also in NCKAP1L deficiency, HLH is linked to impaired pathogen control ( Bucciol et al, 2020 ; Shoham et al, 2003 ). Although speculative, unchecked activation of the inflammasome could also underlie HLH in our patients.…”

Section: Resultscontrasting

confidence: 62%

NCKAP1Ldefects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation

Castro

Rosenzwajg

Carapito

et al. 2020

Journal of Experimental Medicine

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The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage–specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients’ T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.

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Section: Resultscontrasting

confidence: 62%

NCKAP1Ldefects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation

Castro

Rosenzwajg

Carapito

et al. 2020

Journal of Experimental Medicine

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“…Conditional deletion of Cdc42 in the mouse hematopoietic system led to a rapidly fatal myeloproliferative disorder [53]. Finally, a different variant in CDC42 (Y64C) in a human patient has been associated with myelofibrosis observed in adulthood [7]. Therefore, the observed mutation appeared to be potentially relevant to hematopoiesis, although the human phenotype described in this kindred is distinct from what has been reported in animal models and other human patients previously.…”

Section: Functional Studiesmentioning

confidence: 63%

Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction

et al. 2020

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Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.

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“…More recently, including in this and an earlier issue of the Journal of Clinical Immunology, five reports add to the rapidly expanding body of knowledge about this fascinating new disease. The first, by Bucciol and colleagues, describes the oldest patient so far reported, who at 26 years was found to have Takenouchi-Kosaki syndrome with the usual p.Tyr64Cys mutation in a conserved domain of CDC42 required for its GTPase activity [8]. Surprisingly, the patient also had systemic autoinflammation previously associated with NOCARH and other C-terminal region mutations, as well as recurrent severe infections leading to bronchiectasis and death from sepsis.…”

mentioning

confidence: 99%

The Growing Spectrum of Human Diseases Caused by InheritedCDC42 Mutations

2020

J Clin Immunol

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Several recent studies provide valuable new information that expands the spectrum of human disease associated with mutations in CDC42.CDC42, an intracellular member of the Rho-family GTPases, is a key regulator of cell polarity that is highly conserved among eukaryotes (reviewed in [1]). By regulating the assembly of actin cytoskeletal structures in a temporal-spatial manner, CDC42, along with RAC and RHO A, controls cell shape and cell movement. In this way, CDC42 plays an important role in migration and directed functions, processes that are integral for embryonic development, hematopoiesis, or immune system function. CDC42 also influences other functions such as cell growth and proliferation through effects on multiple downstream cell signaling pathways, via actin-based platforms and/or direct interactions of CDC42 with other effectors.As a GTPase, CDC42 functions as an intracellular molecular switch. It cycles between two forms-an active form when bound to GTP and an inactive form when bound to GDP-subject to complex regulation by GTPase activation proteins (GAPs), guanosine exchange factors (GEFs), and guanosine dissociation inhibitors (GDIs). When activated, CDC42 undergoes a conformational change that enables it to associate with membranes and to interact with effector molecules, which in turn undergo their own conformational changes to exert downstream biochemical functions.

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Systemic Inflammation and Myelofibrosis in a Patient with Takenouchi-Kosaki Syndrome due to CDC42 Tyr64Cys Mutation

Cited by 33 publications

References 12 publications

NCKAP1Ldefects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation

NCKAP1Ldefects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation

Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction

The Growing Spectrum of Human Diseases Caused by InheritedCDC42 Mutations

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