Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

Lee, Cindy Eunhee; Fulcher, David A.; Whittle, Belinda; Chand, Rochna; Fewings, Nicole; Field, Matthew A.; Andrews, Daniel; Goodnow, Christopher C.; Cook, Matthew C.

doi:10.1182/blood-2014-06-578542

Cited by 99 publications

(81 citation statements)

References 55 publications

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“…Nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) is a pleiotropic transcription factor present in almost all cell types but its precise roles remain incompletely understood. Two other groups also reported NFKB2 mutations in patients with similar phenotypes making the involvement of NFKB2 in DAVID syndrome highly likely even if the endocrine phenotype was not systematically studied (10,11). However the precise mechanisms whereby this factor may lead to endocrine deficits remain unclear.…”

Section: David Syndrome and Nfkb2mentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

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Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

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Section: David Syndrome and Nfkb2mentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

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“…For instance, congenital mutations in NIK [8] or NEMO [9], both of which encode upstream components of the NF-κB pathways, have demonstrated their importance for NK cell function. Monoallelic mutations in NFKB2, causing a functional haploinsufficiency due to expression of unprocessable p100 precursors have been reported in CVID patients [10][11] and were shown to impair NK cell cytotoxic activity [12]. Recently, monoallelic mutations in NFKB1 leading to p50 haploinsufficiency have also been reported in three CVID families [13].…”

Section: Introductionmentioning

confidence: 99%

NFKB1 regulates human NK cell maturation and effector functions

Lougaris

Patrizi

Baronio

et al. 2017

Clinical Immunology

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NFKB1, a component of the canonical NF-κB pathway, was recently reported to be mutated in a limited number of CVID patients. CVID-associated mutations in NFKB2 (non-canonical pathway) have previously been shown to impair NK cell cytotoxic activity. Although a biological function of NFKB1 in non-human NK cells has been reported, the role of NFKB1 mutations for human NK cell biology and disease has not been investigated yet. We decided therefore to evaluate the role of monoallelic NFKB1 mutations in human NK cell maturation and functions. We show that NFKB1 mutated NK cells present impaired maturation, defective cytotoxicity and reduced IFN-γ production upon in vitro stimulation. Furthermore, human IL-2 activated NFKB1 mutated NK cells fail to upregulate the expression of the activating marker NKp44 and show reduced proliferative capacity. These data suggest that NFKB1 plays an essential novel role for human NK cell maturation and effector functions.

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“…Our work provides insights into how noncanonical signaling is transduced through balancing the amounts of distinct complexes with opposing activities. Increased or reduced processing of p100 causes cancer and defects in immunity (35)(36)(37)(38)(39). In all these cases, aberrant processing could be due to the defect in competition between RelB and the NIK:IKK1 complex for p100 binding as shown here.…”

Section: Discussionmentioning

confidence: 93%

The NF-κB subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100

et al. 2016

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Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

Abstract: Key Points A novel NFKB2 mutation confers a severe B-cell deficiency, but antibody production is partially preserved. Unprocessed p100 results in an IκB-like action on the canonical nuclear factor-κB pathway.

Cited by 99 publications

References 55 publications

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

NFKB1 regulates human NK cell maturation and effector functions

The NF-κB subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100

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