Biomedical Engineering Reference
In-Depth Information
suppresses the skin symptoms. Importantly, purified keratinocytes do not exhibit
hyperproliferation on their own, indicating that the defect is not cell-autonomous.
Thus,
ikk
skin knockout mice demonstrate that hyperproliferation is rather a sec-
ondary event resulting from inflammation and suggest that the critical function of
IKK
β
in epidermal keratinocytes is to regulate mechanisms that maintain the immune
homeostasis of the skin. In contrast to
nemo
(-)
, apoptosis of keratinocytes in
IKK
β
β
skin knockout mice does not contribute substantially to the pathology. Although the
identity of the signals triggering the dermatosis exhibited by IP patients remains
unclear, the data summarized suggest a plausible sequence of events and identify
TNF
as a key participant in both the onset of inflammation and its resolution
through clearance of NEMO
mutated cells by apoptosis.
α
9.3
PHENOTYPES ASSOCIATED WITH HYPOMORPHIC
NEMO MUTATIONS
9.3.1
EDA-ID
B activation is lethal for males
during embryogenesis, females can survive, exhibiting a complex phenotype due to
their mosaic character regarding X-inactivation. Because it is unclear to what extent
the phenotype affecting female patients is directly due to NF-
As indicated, wherease the complete loss of NF-
κ
B dysfunction and
not to the interaction between normal and dying cells, it is difficult to draw a firm
conclusion regarding the consequence of NF-
κ
B deficiency in humans. Therefore,
the question is, what would happen in the case of milder NEMO mutations allowing
males to survive? The answer is provided by a series of recent data that report new
syndromes exclusively affecting male patients. In this case, their single X chromo-
some carries the mutated gene, allowing the direct observation of the physiological
consequences of NF-
κ
B dysfunction in humans.
For years, a rare and complex syndrome exclusively affecting male patients and
associating anhidrotic ectodermal dysplasia and immunodeficiency (EDA-ID;
OMIM # 300291) had been described, but its genetic cause was unknown (see, for
κ
with the association with a perturbed immune response and some similarities with
IP, prompted the analysis of the
nemo
gene. Most patients indeed carried mutations
in
nemo,
but instead of leading to large truncations of the NEMO molecule as
observed in IP, the mutations were missense mutations or small deletions only
affecting the C-terminal zinc finger [18-21] (
Figure 9.1
). Interestingly, all of these
mutations led to reduced but not abolished NF-
κ
B activation, which explains why
affected male patients survive.
Anhidrotic ectodermal dysplasia (EDA) is a well-described pathology charac-
terized by the absence of sweat glands, sparse scalp hair, and missing teeth [22].
Three distinct loci have been shown to be responsible for EDA. The first, located
on the X chromosome (the mutant mouse at this locus is called
tabby
), codes for
two members of the TNF family generated by alternative splicing, EDA-A1, and
EDA-A2 (ectodysplasin), which are produced in tissues of ectodermal origin, such
