RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias

Comrie, William A.; Faruqi, Aiman J; Price, Susan; Rao, V. Koneti; Su, Helen C.; Lenardo, Michael J.

doi:10.1016/j.jaci.2017.11.036

Cited by 35 publications

(24 citation statements)

References 9 publications

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“…Whole-genome sequencing of samples from patients with T-cell-mediated autoimmune lymphoproliferative disease revealed that Rab44 is one of the missense genes [44]. A transcriptome-wide association study indicated that Rab44 was upregulated in white blood cells from patients with atopy [45].…”

Section: Knockout Phenotypes or Diseasesmentioning

confidence: 99%

Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Tsukuba

Yamaguchi

Kadowaki

2021

IJMS

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Rab GTPases are major coordinators of intracellular membrane trafficking, including vesicle transport, membrane fission, tethering, docking, and fusion events. Rab GTPases are roughly divided into two groups: conventional “small” Rab GTPases and atypical “large” Rab GTPases that have been recently reported. Some members of large Rab GTPases in mammals include Rab44, Rab45/RASEF, and Rab46. The genes of these large Rab GTPases commonly encode an amino-terminal EF-hand domain, coiled-coil domain, and the carboxyl-terminal Rab GTPase domain. A common feature of large Rab GTPases is that they express several isoforms in cells. For instance, Rab44’s two isoforms have similar functions, but exhibit differential localization. The long form of Rab45 (Rab45-L) is abundantly distributed in epithelial cells. The short form of Rab45 (Rab45-S) is predominantly present in the testes. Both Rab46 (CRACR2A-L) and the short isoform lacking the Rab domain (CRACR2A-S) are expressed in T cells, whereas Rab46 is only distributed in endothelial cells. Although evidence regarding the function of large Rab GTPases has been accumulating recently, there are only a limited number of studies. Here, we report the recent findings on the large Rab GTPase family concerning their function in membrane trafficking, cell differentiation, related diseases, and knockout mouse phenotypes.

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Section: Knockout Phenotypes or Diseasesmentioning

confidence: 99%

Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Tsukuba

Yamaguchi

Kadowaki

2021

IJMS

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“…The clinical phenotype of RELA haploinsufficiency was expanded in 2018 when Comrie et al 165 . identified a heterozygous de novo nonsense variant in RELA in a male individual with an ALPS‐like phenotype.…”

Section: Primarily Inflammationmentioning

confidence: 99%

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Schnappauf

Aksentijevich

2020

Journal of Leukocyte Biology

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NF-B is a master transcription factor that activates the expression of target genes in response to various stimulatory signals. Activated NF-B mediates a plethora of diverse functions including innate and adaptive immune responses, inflammation, cell proliferation, and NF-B is regulated through interactions with I B inhibitory proteins, which are in turn regulated by the inhibitor of B kinase (IKK) complex. Together, these 3 components form the core of the NF-B signalosomes that have cell-specific functions which are dependent on the interactions with other signaling molecules and pathways. The activity of NF-B pathway is also regulated by a variety of post-translational modifications including phosphorylation and ubiquitination by Lys63, Met1, and Lys48 ubiquitin chains. The physiologic role of NF-B is best studied in the immune system due to discovery of many human diseases caused by pathogenic variants in various proteins that constitute the NF-B pathway. These disease-causing variants can act either as gain-of-function (GoF) or loss-of-function (LoF) and depending on the function of mutated protein, can cause either immunodeficiency or systemic inflammation. Typically, pathogenic missense variants act as GoF and they lead to increased activity in the pathway. LoF variants can be inherited as recessive or dominant alleles and can cause either a decrease or an increase in pathway activity. Dominantly inherited LoF variants often result in haploinsufficiency of inhibitory proteins. Here, we review human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF-B pathway and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.

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“…The clinical phenotypes associated with RELA haploinsufficiency have recently been expanded. There is a report of a 5-year-old boy who was misdiagnosed with autoimmune lymphoproliferative syndrome [48]. The initial presentation was with splenomegaly, refractory immune thrombocytopenic purpura, anaemia and neutropenia.…”

Section: Relopathiesmentioning

confidence: 99%

Hereditary systemic autoinflammatory diseases and Schnitzler’s syndrome

2019

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The systemic autoinflammatory diseases are disorders of the innate immune system distinguished by severe inflammation resulting from dysregulation of the innate immune system. Hereditary fever syndromes, such as FMF, TNF receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes and mevalonate kinase deficiency, were the first group of systemic autoinflammatory diseases for which a genetic basis was established, between 1999 and 2001. Currently according to the latest report of the international union of immunological societies, 37 separate monogenic disorders were classified as autoinflammatory. In addition to the abovementioned monogenic conditions, we describe Schnitzler’s syndrome, a well-defined, acquired autoinflammatory condition without a clear genetic basis. For the purposes of this review, we discuss several conditions defined by the latest consensus process as systemic autoinflammatory diseases. We focus on those disorders where recent studies have contributed to further phenotypic characterization or had an impact on clinical management.

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RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias

Cited by 35 publications

References 9 publications

Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Hereditary systemic autoinflammatory diseases and Schnitzler’s syndrome

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