The NF-jB signalling pathway in human diseases:
from incontinentia pigmenti to ectodermal
dysplasias and immune-deficiency syndromes
Asma Smahi1,*, Gilles Courtois2, Smail Hadj Rabia1, Rainer Do ¨ffinger3, Christine Bodemer1,
Arnold Munnich1, Jean-Laurent Casanova3and Alain Israe ¨l2
1De ´partement de Ge ´ne ´tique et Unite ´ de Recherches sur les Handicaps Ge ´ne ´tiques de l’Enfant INSERM UR-393,
Ho ˆpital Necker, 149 rue de Se `vres, 75743 Paris Cedex 15,2Unite ´ de Biologie Mole ´culaire de l’Expression Ge ´nique,
FRE 2364 CNRS, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15 and3Unite ´ de Ge ´ne ´tique Humaine des
maladies infectieuses, INSERM UR-550, Faculte ´ de Me ´decine Necker, 156 rue de Vaugirard, 75730 Paris Cedex 15,
Received July 10, 2002; Accepted July 15, 2002
The transcription factor NF-jB regulates the expression of numerous genes controlling the immune and
stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia
pigmenti (IP) is the first genetic disorder to be ascribed to NF-jB dysfunction. IP is an X-linked dominant
genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-jB essential
modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-jB
activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to
at least three genes also involved in NF-jB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and
EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by
ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-jB
activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-jB cascade.
Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with
immunodeficiency (EDA–ID), whilst stop codon mutations cause a more severe phenotype associating
EDA–ID with osteopetrosis and lymphoedema (OL–EDA–ID). The immunological and infectious features
observed in patients result from impaired NF-jB signalling, including cellular response to LPS, IL-1b, IL-18,
TNF-a, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-jB in
the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA
not associated with mutations in NEMO will possibly implicate other components of the NF-jB signalling
THE NF-jB SIGNALLING CASCADE
The transcription factor NF-kB regulates the expression of
genes controlling the immune and stress responses, inflamma-
tory reaction, cell adhesion, and protection against apoptosis
(for a review, see 1). NF-kB is composed of homo- or
heterodimers of five proteins belonging to the Rel family. In the
vast majority of cell types, NF-kB is kept inactive in the
cytoplasm through association with inhibitory proteins of the
IkB family: IkBa, IkBb and IkBe. IkB molecules are
phosphorylated on two critical serine residues in response to
multiple stimuli such as cytokines, various stress signals, viral
and bacterial infections. The most extensively studied signals
are tumour necrosis factors (TNF), interleukin-1 (IL-1) and
lipopolysaccharide (LPS). This modification allows its recogni-
tion by an ubiquitination complex, and, following polyubiqui-
tination, IkBs are degraded by the proteasome machinery. As a
consequence, free NF-kB enters the nucleus and activates
transcription of its target genes (Fig. 1) (2).
For many years, the kinase phosphorylating IkB (IKK for
IkB kinase) has remained elusive. Upon biochemical fractiona-
tion, it was eventually identified as a high-molecular-weight
complex migrating around 700–900kDa and containing two
related catalytic subunits: IKKa/IKK1 and IKKb/IKK2. IKK1
and IKK2 are highly homologous kinases, both containing an
N-terminal kinase domain, a helix–loop–helix (HLH) and
*To whom correspondence should be addressed. Tel: þ33 144495161; Fax: þ33 147348514; Email: firstname.lastname@example.org
# 2002 Oxford University Press Human Molecular Genetics, 2002, Vol. 11, No. 202371–2375
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a leucine zipper domain (LZ) (for a review, see 2 and 3).
Another of its components, NEMO (NF-kB essential modu-
lator), also known as IKKg, has been subsequently identified
through various approaches (4,5). NEMO, in contrast to IKK1
and IKK2, exhibits no catalytic properties but acts as a
structural and regulatory subunit of the IKK complex. Cell
lines defective for NEMO do not activate NF-kB in response to
most stimuli, demonstrating its essential role in the NF-kB
activation process. In the absence of NEMO, a smaller complex
(400kDa) that contains both IKK1 and IKK2 could be found in
mutant cell lines, but this complex was unresponsive to
external stimuli. Structure prediction of NEMO indicates a high
coiled-coil content and a C-terminal zinc finger. Deletion
analysis has demonstrated that the N-terminal region of NEMO
interacts with the C-terminal region of the IKK kinases, and
that the C-terminal zinc finger is required for NF-kB activation
by cytokines and LPS. The stoichiometry of the complex is
Genetic models in which individual NF-kB or IkB proteins
have been deleted in mice have confirmed the essential role
played by NF-kB in the immune, inflammatory and apoptotic
responses (6). Complete inhibition of NF-kB activity results in
prenatal lethality due to TNF-induced liver apoptosis. Other
knockouts (KOs) that alter but not abolish NF-kB activity all
lead to multiple defects of the immune system affecting most
cell lineages, often connected with abnormal control of the
HUMAN DISEASES RELATED TO THE
Incontinentia pigmenti (IP; MIM308300) is a rare X-linked
dominant genodermatosis antenatally lethal in males. Affected
females present with Blashko linear skin lesions occurring in
four successive, sometimes overlapping, stages: erythema,
vesicles, pustules (stage 1), verrucous lesions (stage 2),
hyperpigmentation (stage 3), and pallor and scarring (stage 4)
(7). Association with developmental anomalies of teeth, eyes,
hair and the central nervous system have been reported. IP
females show a completely skewed pattern of X inactivation,
which results from selection of cells expressing the non-
mutated X chromosome (8). The study of cells derived from
spontaneously aborted fetuses revealed a complex rearrange-
ment of the NEMO gene that results in the deletion of exons
4–10, potentially coding for a shortened ?130-amino-acid
protein unable to elicit an NF-kB response. This recurrent
rearrangement accounts for 85% of IP patients (9,10), and
affected cells are indeed refractory to NF-kB-activating stimuli.
Furthermore, IP cells are highly sensitive to TNF-induced
apoptosis, suggesting a role for this cytokine in the develop-
ment of IP lesions, and in associated anomalies as well
Ectodermal dysplasia (ED) is a clinically heterogeneous
condition characterized by the abnormal development of
ectoderm-derived structures, namely teeth, hair, nails and
eccrine sweat glands (11). More than 170 phenotypes have
hitherto been described. The hypohidrotic/anhidrotic form
(HED/EDA) is characterized by the association of sparse hair,
abnormal or missing teeth, and inability to sweat, which
is responsible for life-threatening brain-damaging episodes due
to hyperthermia (12). This clinically homogeneous phenotype
has been ascribed to at least four genes, and three modes
of inheritance have been reported: X-linked recessive (MIM
305100) and autosomal dominant and autosomal recessive
(MIM 224900). The X-linked form is the most common, and
is caused by mutations in the ectodysplasin gene (EDA1),
a member of the TNF cytokine superfamily (13,14). Autosomal
forms are caused by mutations in the EDA3 gene (chromosome
2q13), which encodes EDAR, a protein belonging to the TNF-
receptor superfamily (TNFR) (15,16). EDAR is the receptor of
the EDA-A1 ectodysplasin isoform (17). This gene is
responsible for both dominant and recessive HED/EDA.
Recently, a mutation in the EDARADD gene (EDAR-associated
death domain, chromosome 1q42) has been reported in another
autosomal recessive form of HED/EDA (18). During hair
Figure 1. A simplified overview of the NF-kB activation process. In response to
multiple stimuli, IKK kinase (composed of catalytic subunits IKK1 and IKK2
and regulatory subunit NEMO) is activated. IKK phosphorylates NF-kB inhi-
bitory molecule (IkB), leading to its degradation by the proteasome and release
of NF-kB dimer (the species composed of relA and p50 subunits is shown
here). NF-kB translocates into the nucleus, where it regulates the expression
of hundreds of genes. The NEMO subunit of IKK appears to be a convergence
point, since its absence is associated with a lack of NF-kB activation in
response to most known stimuli.
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follicle morphogenesis and in the epidermis, EDAR is activated
by EDA and uses EDARADD as an adapter to build an
intracellular signal-transducing complex that leads to NF-kB
activation (18,19). Biochemical analysis has shown that NF-kB
activation by EDAR is NEMO-dependent (20). Not unexpect-
edly, patients carrying mutations in the NEMO gene also
presented with EDA (20–22). EDA-A2, the second isoform of
ectodysplasin, binds to XEDAR, a novel member of the TNF-R
superfamily, which also activates NF-kB (23). Interestingly, a
mutation in the XEDAR gene (X chromosome) has been
recently identified in an HED/EDA patient (S.A. Wisniewski,
B. Marszalek, K. Kobielak and W.H. Trzeciak, European
Human Genetics Conference, May 2002). Mutations in the
EDA, EDAR, XEDAR and NEMO genes reveal a new signal
transduction pathway participating in differentiation of skin
Anhidrotic ectodermal dysplasia with immunodeficiency
A small number of male EDA patients have been reported with
severe infections with pyogenic bacteria (e.g. Streptococcus
pneumoniae and Staphylococcus aureus) and specific poly-
saccharide antibody deficiency (24,25), pointing towards a
possibly distinct X-linked recessive entity causing EDA with
impaired antibody response to polysaccharides (XL–EDA–ID).
Following the recent report of a surviving male patient with a
NEMO mutation (MIM 300248) (10), various hypomorphic
NEMO mutations were found to cause distinct conditions.
Mutations in the coding region are associated with the EDA–ID
phenotype (MIM 300291), whilst stop codon mutations cause a
clinically more severe syndrome associating osteopetrosis and/
or lymphoedema with EDA–ID (OL–EDA–ID; MIM 300301)
(9,10,20–22,26,27). Hence loss-of-function mutations cause IP,
while hypomorphic mutations cause two allelic conditions,
namely XL–OL–EDA–ID and EDA–ID.
EDA–ID males suffer from unusually severe life-threatening
and recurrent bacterial infections of lower respiratory tract,
skin, soft tissues, bones and gastrointestinal tract, as well as
meningitis and septicemia in early childhood. The causative
pathogens have most often been Gram-positive bacteria
(S. pneumoniae and S. aureus), followed by Gram-negative
bacteria (Pseudomonas spp. and Haemophilus influenzae) and
mycobacteria. Interestingly, two children had Pneumocystis
carinii infections (PCP), suggesting a more profound immu-
nodeficiency. The two XL–OL–EDA–ID patients had a
particularly severe ID, since they acquired environmental
mycobacterial infections in their first year of life and died.
As a comparison, severe combined immunodeficiency (lacking
T cells) or interferon-g (IFN-g) receptor deficiency does not
cause environmental mycobacteriosis so early in life.
Most patients have hypogammaglobulinaemia with low
serum IgG (or IgG2) levels, while the levels of other
immunoglobulin isotypes (IgA, IgM and IgE) varied. A
number of EDA–ID patients have been described with elevated
serum IgM levels (the ‘hyper-IgM’ phenotype) (20–22). Some,
but not all, CD40-mediated signals are NEMO-dependent in B
cells. In some patients, B cells have an impaired ability to
switch in response to CD40 ligand (CD40L), and in others the
switch is normal but there is an impaired proliferation and
activation that also results in a ‘hyper-IgM-like’ phenotype.
The impaired antibody response to polysaccharide antigens is
the most consistent laboratory feature. When compared with
these B-cell anomalies, patients with XL–EDA–ID and XL–
OL–EDA–ID have normal T-cell proliferation to mitogens and
antigens. Recently, impaired NK activity has been reported in
some (28) but not all (20,27) patients with EDA–ID. The
immunological abnormalities may be related to the type of
NEMO mutation involved.
Thus, the immunological and infectious features of the
patients result from an impaired cellular response of peripheral
blood lymphocytes to LPS, IL-1b, IL-18, TNF-a, and CD40L
(20). Other NF-kB-dependent pathways are likely to be
affected as well. Indeed, NEMO-dependent NF-kB activation
is important to the signalling pathways downstream of Toll
receptors (Tlr) (29). These patients exhibit poor inflammatory
response, also due to impaired cellular responses to pro-
inflammatory cytokines (IL-1b, IL-18 and TNF-a) (20).
Impaired response to LPS via Tlr4 and partially impaired
CD40 signalling could explain the susceptibility of these
patients to infections with Gram-negative bacteria and P. carinii,
respectively. Infections by Gram-positive bacteria may result
from impaired responses to IL-1b, IL-18, Tlr2 or other NF-kB-
dependent signalling pathways. The occurrence of severe
mycobacterial disease in these patients could be due
to impaired IL-1b- and IL-18-dependent induction of IFN-g,
impaired cellular responses to IFN-g-inducible TNF-a, or
impaired signalling through Tlrs.
MOUSE MODELS OF NF-jB-RELATED DISEASES
NEMO-deficient mice have been produced in several labora-
tories. They are characterized by early lethality around
embryonic day 12 in males (30–32). Death is due to massive
liver apoptosis, a feature that has been previously observed in
other KO models involving critical components of the NF-kB
signalling pathway, such as relA or IKK2 (33–36). Whether
lethality in male IP patients results from the same problem
remains to be determined. Heterozygous NEMO-deficient
female mice survive until birth, but, shortly after, exhibit a
transient dermatosis, characterized by patchy skin lesions with
massive granulocyte infiltration, hyperproliferation and in-
creased apoptosis of keratinocytes (30–32). The whole process
shares striking similarities with what is seen in IP patients.
The only notable difference concerns the high level of
morbidity that is observed in female mice, around postnatal
day 6–10 (P6–P10), a feature that has never been observed in
The recent generation of mice exhibiting a specific deletion
of IKK2 in the epidermis has also provided important
information regarding the consequences of NF-kB dysfunction
in skin, and may be relevant to IP dermatosis. Because IKK2
KO mice die during early development, studying the postnatal
role of IKK2 is presently impossible. A conditional IKK2 KO
in the epidermis has been produced first by targeting the IKK2
locus with loxP sites then by crossing the mice with a strain
expressing keratin 14 (K14)-driven Cre recombinase (37).
Because K14 is specifically expressed in epidermis and hair
follicles, these mice develop normally until P4–P5, when their
skin starts to become hard and inflexible. This phenotype
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progresses rapidly, and by P7–P8 the mice exhibit a highly
rigid, shell-like skin with widespread scaling. At this stage, the
mice become runted, and they subsequently die between P7 and
P9. Histological analysis of skin sections at P7 shows
epidermal thickening with loss of the granular layer, pro-
nounced hyperkeratosis, focal parakeratosis, subcorneal pustule
formation, increased cellularity and dilated blood vessels in the
dermis. Interestingly, crossing the mice with TNFR KO mice
suppresses these features, demonstrating the essential role of
TNF in this process and suggesting that keratinocyte
hyperproliferation is a secondary event resulting from
A major difference between NEMO and IKK2 skin KO mice
is the high level of keratinocyte apoptosis observed in the
former but not in the latter, thus representing a hallmark of IP. It
is likely that the early stages of the disease in mouse models
share many similarities with IP and deserve particular attention.
Analysis of IKK2 skin KO mice has demonstrated that NF-kB
plays an essential role in controlling skin homeostasis, but the
nature of the signal/change that triggers dermatosis remains
unclear. Despite this uncertainty, the crucial role played by
TNF in the development of the disease may suggest novel
therapeutic approaches to treat the disease in IP and EDA–ID
NF-kB dysfunction in humans appears to be associated with a
broad range of defects involving many organs. This feature
results from the central role played by this transcription factor
in many signalling pathways critical for the immune, inflam-
matory and anti-apoptotic responses. The defects concerning
the epidermis are of particular interest, since they confirm and
extend the notion that NF-kB plays a key role in both
homeostasis of the epidermis and development of skin
appendages. IP is caused by lethal loss of NEMO function
while XL–EDA–ID and XL–OL–EDA–ID are caused by
hypomorphic NEMO mutations. EDA–ID is clinically hetero-
genous, since some patients have overwhelming clinical
diseases caused by several microorganisms, whereas others
seem to be susceptible to a limited number of species. Finally,
most EDA elucidated to date involve ectodysplasin (EDA), its
receptor (EDAR) or adaptor (EDARADD) in a signal-
transducing complex that leads to NF-kB activation.
Unravelling the molecular bases of other forms of EDA not
associated with mutations in NEMO will possibly implicate
other components of the NF-kB signaling pathway.
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