What are the Six Key Genes in the Ectodermal Dysplasias?
EDA, EDAR, EDARADD, WNT10A, IKBKG (aka NEMO) and TP63
One question we are often asked is about the differences between the key genes involved in the
different types of ectodermal dysplasia (ED). There are many different types of ED and many different
genes can be involved. There is a small number of key genes that are most typically involved as well
as many rare genes.
All these genes are present in everyone, but changes in the code of that gene can cause problems if
the code change alters the genetic instruction. So, when a particular gene is said to be involved in
one individual with one specific type of ED, it means that a change in that gene is responsible for
their form of ED. In families where more than one family member has ED, they almost always share
the same change in the same gene.
Genes
A gene can be thought of as an instruction – as in a recipe – for how the body should assemble itself
and how it can function.
Genes consist of long runs (sequences) of the four different building blocks of DNA (Deoxyribose
Nucleic Acid) A, C, G and T. The genes come in matching pairs, with one gene of each pair coming
from each parent. The 20,000 or so different types of gene are all made of the DNA (those long
strings of A, C, G and T) and are carried in the 23 chromosomes present in the sperm and the 23
chromosomes present in the egg that went to make each of us, with our 46 chromosomes.
See the genetics section on our website https://edsociety.co.uk/what-is-ed/genetics/
Chromosomes
An important fact about genes is that this story – that we each carry two complete sets of all the
genes – is only strictly true for girls and women. Twenty-two of the different types of chromosome
are the same in boys and girls; they are the autosomes, 1-22. The 23rd pair are the sex chromosomes,
known as X and Y. Females carry two X chromosomes (one from mother and one from father) while
males have only one X chromosome (from mother) with, in addition, a much smaller chromosome
known as the Y chromosome (from father). Females therefore carry two of each of the chromosomes
1-22 and two X chromosomes. Boys, however, have only one X chromosome plus one Y chromosome.
The X chromosome is an average-sized chromosome that carries many different genes important in
many aspects of development and function, not only for sex and reproduction. The other sex
chromosome, present in a boy, is the Y chromosome. This is important for development of male
characteristics but does not have all of the other genes that are usually present on the X
chromosome.
Dominant, Recessive and Sex-Linked
We must also remember that an alteration in a gene (a mutation) can be inherited or can occur,
purely by chance, as a new event. The effect of a gene change depends on the exact code change
and the gene involved. Sometimes, both copies of a gene need to be altered for there to be any
effect: a single functioning copy of many genes is sufficient to avoid a problem. These gene
alterations are known as “recessive” because they may seem to be hidden in those who carry a single
alteration and are unaffected. Sometimes, gene “carriers” like this may have very mild problems.
Other genetic alterations lead to a change in the development or function of the body even when
one copy of the gene is perfectly intact. With such a gene, a single altered copy is enough to cause
an effect: such a gene alteration is called “dominant” and will usually show itself (its effects may be
apparent at birth for some conditions or, for others, not until well into adult life).
This description of genetics misses out some of the complications – the fudges and blurring – but is
broadly correct. However, we must say more about the sex chromosomes, where this distinction
between dominant and recessive genetic changes is different. Because a boy has only one X
chromosome, he will show any gene alteration that arises in a gene on his one and only X
chromosome. A girl or woman is much less likely to show the effects of a gene alteration on the X,
because she has a second copy of the same gene on her other X chromosome.
However, the story gets more complicated still. Half a century ago, a genetics researcher Mary Lyon realised that only one of the two X chromosomes in a female mammal (including female humans) functions fully in any one cell (cells each contain the complete set of genes and chromosomes). Most of the genes on one of the two X chromosomes in a female are switched off – i.e. inactivated. So, as an example, a woman’s skin consists of patches where her mother’s X chromosome is the one that functions, and other areas of skin where it is her father’s X chromosome that is working, and the decision as to
which X chromosome works in which cells in her body or on her skin is random and is made in the
embryo, long before birth.
So a girl may still show signs of a sex-linked condition (caused by changes
in a gene on the X chromosome) if the X chromosome with the intact copy of the gene is inactivated
in a part of the body where the effects can be seen.
Different genes in different types of ectodermal dysplasia (ED)
So, leaving aside the sex chromosomes, we each inherit two complete sets of genes. The Human
Genome Organisation (HUGO) designates an official name and symbol (an abbreviation of the name)
for each known human gene.
Here, we are going to mention just six of these genes, which are often involved in some of the ED
conditions. Many more are mentioned in the Tables you can find elsewhere on the EDUK website.
Hypohidrotic ectodermal dysplasia (HED): EDA, EDAR, EDARADD and Part One of
IKBKG (also known as NEMO)
First, we will mention the most common type of ED, known as hypohidrotic ED (HED). In this
condition, reduced sweating is usually a major feature as well as effects on the teeth and hair, and
sometimes also the nails. A key step in development of these body structures requires a specific
triggering signal to be sent and received within the developing skin. This signal is a protein molecule
(ectodysplasin-A) encoded by a gene on the X chromosome (the EDA gene). The information
encoded in the gene is used to make the protein molecule, so an alteration in the EDA gene alters
the ectodysplasin-A protein signal and may interfere with its function. The signal is received by a
signal receptor molecule embedded in the cell membrane of other cells nearby. This ectodysplasinA receptor protein molecule is encoded by a gene (EDAR) and, when ectodysplasin-A binds to its
receptor, it triggers the next steps in developing the affected structures (teeth, hair, sweat glands
etc).
This signalling step is critical for interactions between two embryonic cell layers called the
ectoderm and the mesoderm. In the early embryo, these cell layers form the basis for many of the
body’s organs and tissues including the skin and the teeth.
Because the EDA gene is on the X, changes in this gene will have an effect more often and more
severely in boys than in girls. Females may show no signs at all, or they may show some signs but
these will usually be less marked and often only present in some areas of the body (e.g. changes to
only some teeth, patchy sweating and patchy changes to the hair on the scalp and the body).
The effects of changes in the EDAR gene are very similar to the effects of changes in EDA, because
they are involved in the same step in development, but they vary in how serious they are. Some
changes are rather mild and cause no problems, unless present on both copies of the gene, while
others are more disruptive and having such a change in only a single copy of the EDAR gene will lead
to clear signs of HED. In other words, the changes in EDAR are sometimes “recessive” and sometimes
“dominant”. Changes in the EDAR gene can affect men and women equally as this gene is situated
on chromosome 2, not on the X chromosome.
Another gene, whose protein product sits close to the ectodysplasin-A receptor (the EDAR gene’s
protein product), is the EDARADD gene. The EDARADD protein supports the action of the
ectodysplasin-A receptor, although changes in this gene are very uncommon as a cause of HED.
The fourth gene to be mentioned as important in HED, and also very rare, is the IKBKG or NEMO
gene. Some changes in this gene, also on the X chromosome, will cause a very rare but unusually
severe type of HED in boys, with incomplete manifestations in girls as in the usual EDA-type of XHED.
The physical features of the condition are much the same as in the other types of HED, but this form
is often complicated by a dangerous tendency to severe, sometimes life-threatening, infections. The
EDA type of XHED can also lead to frequent chest infections, but it is especially severe in the rare,
IKBKG/NEMO subtype of HED. Management of this condition must involve an experienced
immunology specialist.
Incontinentia Pigmenti (IP): Part Two of IKBKG (or NEMO)
A different, more severe type of alteration in the IKBKG or NEMO gene just discussed causes a very
different condition usually affecting girls only. In males their development is usually so severely
damaged that a pregnancy with an affected male will miscarry quite early. An affected female embryo
only survives to be born because half of her cells express the intact copy of the gene, as she has two
X chromosomes. That allows her to survive, whereas an affected male embryo does not have even a
single intact copy of the gene, as he only has one X chromosome.
This type of alteration in the gene leads, in the female, to the death of part of the outer epithelial
layer (thin tissue forming the surface skin) of the affected areas of skin. These patches of skin
epithelium are replaced first by angry blisters often present at birth or soon afterwards and then by
pigmented tissue (coloured patches of skin). Over time, these areas of healed blistering and
pigmentation are then slowly replaced by scar tissue that is pale, hairless and does not sweat; these
scars can be seen as pale streaks in the skin of adult women who were affected as infants.
There can also be damage to certain other body structures where this gene is important in early development, including the eyes and the teeth. It is of great importance that newborns with IP have their eyes examined before they leave hospital and then have eye checks every 3 months until one year of age,
every 6 months until 3 years of age and annually thereafter.
TP63 gene: ED plus Limbs, Palate, Eyes, …
The protein produced by the TP63 gene is a transcription factor: it sits in the cell nucleus (the separate
part of the cell where the chromosomes are found) acting on other genes to control how they are
expressed. It is involved in the development of many different parts of the body, not only those
involved as key features of an ectodermal dysplasia (like hair, teeth, nails and sweat glands).
Other parts of the body that can be involved include the palate and the developing limb buds, so
that patients where this gene has a problem may have a cleft palate and syndactyly (fusion of the
fingers or toes) or ectrodactyly (split hand and/or split foot). Development of the breasts may also
be disturbed, and the lacrimal glands of the eye and more generally the tissues around the eyes. The
exact pattern of problems that can be caused varies with the particular change in the gene, so
different changes in TP63 can lead to a number of different “syndromes” including EEC syndrome,
AEC syndrome, Rapp-Hodgkin syndrome, ADULT syndrome and Limb-Mammary syndrome. These
could all be regarded as, at root, different expressions of the same condition – or else as distinctly
different conditions but where different changes in the same gene happen to be responsible for
causing them all.
The WNT10A Gene
Finally, we come to WNT10A. The protein product of this gene is another signalling molecule that
influences the expression of other genes within the cell nucleus. It is involved in a different
developmental pathway from either EDA, EDAR, EDARADD and IKBKG / NEMO or from TP63.
However, it also influences the EDA gene pathway so that changes in WNT10A cause slightly different
features of ED from XHED or EDAR. The protein produced from the WNT10A gene plays a role in the
development of many parts of the body. However, the WNT10A protein is particularly important for
the formation and shaping of both baby (primary) teeth and adult (permanent) teeth, which tend to
be more evenly affected than in XHED. The teeth tend to be a bit small but evenly spaced and without
being so misshapen as in XHED. Effects on the hair and nails are often less marked than in EDA and
there may be variable sweating problems. This is sometimes recognised by researchers as a “mild
variant HED”.