The Same IκBα Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes

Janssen, Riny; Wengen, Annelies van; Hoeve, Marieke A.; Dam, Monique ten; Burg, Miriam van der; Dongen, Jacques J. M. van; Vosse, Esther van de; Tol, Maarten van; Bredius, Robbert G. M.; Ottenhoff, Tom H. M.; Weemaes, C.M.R.; Dissel, Jaap T. van; Lankester, Arjan C.

doi:10.1084/jem.20040773

Cited by 133 publications

(99 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results suggest that the NF-kB signal transduction pathway is disturbed in both cell types. The degree of GH insensitivity in the present patient is similar to that reported by Wu et al, but the immune problems in the patient with the IkBa mutation were far more severe (16,31). Our patient had a mild hypogammaglobulinemia and recurrent infections responding to antibiotics, suggesting that the observed impairment of immunity is mainly limited to the humoral immune response.…”

Section: Discussionsupporting

confidence: 75%

A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

Mul

Wu²,

Paus³

et al. 2012

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IkB mutation suggests that the NF-kB pathway may interact with STAT5B signaling. Design: Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21-25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance. Methods and results: In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-kB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-kB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-kB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells. Conclusions: We conclude that the 17q21-25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-kB signaling, possibly due to PRKCA mRNA overexpression.

show abstract

Section: Discussionsupporting

confidence: 75%

A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

Mul

Wu²,

Paus³

et al. 2012

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…In our case, these mechanisms enable Nkx3.2 to cause persistent NF-B activation, which, in turn, supports chondrocyte survival. In addition, we interestingly observed that functionally intact IKK␤ and NEMO are required for viability maintenance in multiple (16,17,28,43). While these previous studies did not address molecular mechanisms responsible for constitutive IKK and/or NF-B activation in chondrocytes, our current study may provide a molecular explanation as to how a nuclear factor such as Nkx3.2 can enable steady-state IKK activation leading to constitutive NF-B activation, which can be associated with cell viability maintenance in chondrocytes (28,43).…”

Section: Discussionmentioning

confidence: 94%

Exogenous Signal-Independent Nuclear IκB Kinase Activation Triggered by Nkx3.2 Enables Constitutive Nuclear Degradation of IκB-α in Chondrocytes

Yong

Choi

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

NF-B is a multifunctional transcription factor involved in diverse biological processes. It has been well documented that NF-B can be activated in response to various stimuli. While signal-inducible NF-B activation mechanisms have been extensively characterized, exogenous signal-independent intrinsic NF-B activation processes remain poorly understood. Here we show that I B kinase ␤ (IKK␤) can be intrinsically activated in the nucleus by a homeobox protein termed Nkx3.2 in the absence of exogenous IKK-activating signals. We found that ubiquitin chain-dependent, but persistent, interactions between Nkx3.2 and NEMO (also known as IKK␥) can give rise to constitutive IKK␤ activation in the nucleus. Once the Nkx3.2-NEMO-IKK␤ complex is formed in the nucleus, IKK␤-induced Nkx3.2 phosphorylation at Ser148 and Ser168 allows ␤TrCP to be engaged to cause I B-␣ ubiquitination independent of I B-␣ phosphorylation at Ser32 and Ser36. Taken together, our results provide a novel molecular explanation as to how an intracellular factor such as Nkx3.2 can accomplish persistent nuclear IKK activation to enable intrinsic and constitutive degradation of I B in the nucleus in the absence of exogenous NF-B-activating signals, which, in turn, plays a role in chondrocyte viability maintenance.NF-B regulates expression of a variety of genes associated with immune responses, proliferation, differentiation, and apoptosis (21, 23, 39). Numerous studies have described in detail the molecular mechanisms of signal-dependent NF-B activation. In particular, it is well established that diverse NF-B-activating signals trigger I B kinase ␤ (IKK␤) activation in the cytoplasm to permit signal-dependent I B-␣ phosphorylation, which, in turn, causes its ubiquitination and proteasomal degradation, leading to 11,13,18,21,23,39). While these extensive studies pertain to the signal-inducible NF-B activation process, exogenous signal-independent intrinsic NF-B activation mechanisms are largely unknown.Nkx3.2 (also termed Bapx1) is initially expressed in chondrocyte precursor cells during development, and later, its expression is maintained in chondrocytes of various skeletal elements (19,20,25,29,37,47). We have previously demonstrated that Nkx3.2 supports chondrocyte survival by constitutively activating p65-RelA, leaving p105 and p100 NF-B unaffected (28). However, it remains to be understood how Nkx3.2, a nuclear homeobox protein, can indeed trigger constitutive I B degradation and give rise to intrinsic NF-B activation in chondrocytes in the absence of exogenous NF-Bactivating signals.It has been suggested that polyubiquitin chains play a role in creating multiprotein complexes in signal-inducible NF-B activation pathways (4,9,27,34,35,41,48). For instance, the ability of NEMO (also known as IKK␥) to recognize and interact with polyubiquitin chains has been shown to be critical for NEMO to establish functionally active IKK complexes in the cytoplasm in response to NF-B-activating signals (4,9,34,41,48). While these findings pertain to signal-inducible ev...

show abstract

“…61,62 This new autosomal dominant form of EDA-ID shares many similarities with NEMO-related EDA-ID, but is also characterized by an unusual feature. It is associated with severely impaired T cell proliferation, something that is not observed with NEMO mutated patients.…”

Section: Eda-id (Autosomal Dominant Form)mentioning

confidence: 99%

NF-κB-related genetic diseases

Courtois

Smahi

2006

Cell Death Differ

View full text Add to dashboard Cite

The recent identification of genetic diseases (incontinentia pigmenti, anhidrotic ectodermal dysplasia with immunodeficiency and cylindromatosis) resulting from mutations affecting components of the nuclear factor-jB (NF-jB) signaling pathway provides a unique opportunity to understand the function of NF-jB in vivo. Besides confirming the importance of NF-jB in innate and acquired immunity or bone mass control, analysis of these diseases has uncovered new critical roles played by this transcription factor in the development and homeostasis of the epidermis and the proper function of lymphatic vessels. In addition, the identified mutations will help understanding at the molecular level how NF-jB is activated in response to cell stimulation.

show abstract

The Same IκBα Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes

Cited by 133 publications

References 27 publications

A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

Exogenous Signal-Independent Nuclear IκB Kinase Activation Triggered by Nkx3.2 Enables Constitutive Nuclear Degradation of IκB-α in Chondrocytes

NF-κB-related genetic diseases

Contact Info

Product

Resources

About