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The text of this BLAST project
exercise is copyrighted under the name of IUPUI Student Sheri Groen-Roberts
2003, as part of the IUPUI biology course Biotechnology
540. There are no restrictions on its use by educators or by non-profit institutions
as long as its content not modified, proper copyright acknowledgement is retained,
and this statement is not removed.
Epidermolysis Bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types
Epidermolysis Bullosa (EB) is a rare genetic disease characterized by extremely
fragile skin and recurrent blister formation. An afflicted person's skin is
so fragile, that it can tear or blister from what is normally routine activity
or contacts. These persons must take care in the kinds of clothing they wear
as things like elastics can cause unbearable chafing and even very warm temperatures
and humidity can exacerbate this condition. The disease ranges in its severity
and body location, depending on where on the chromosome the mutation occurs.
Some people experience only minimal chafing while others may have blisters
forming in their esophagus and stomach.
Approximately 2 out of 100000 Americans are afflicted with this disease. This
disease in typically inherited as autosomal dominant. In rare situations,
such as consanguinity, it can be inherited as autosomal recessive.
Children with this disorder are sometimes referred to as possessing 'butterfly'
skin as it is so fragile and delicate.
- The KRT5 gene was first cloned by Lersch
and Fuchs in 1988. The accession number for the KRT5 gene is NM_000424.
The mRNA is 2301 bp in length.
The KRT14 gene was first cloned by Rosenberg et al also in 1988. The accession
number for KRT14 is NM_000526. The mRNA is 1634 bp in length.
- The genetic nature of EB involves a missense mutation on KRT5 or KRT14.
This results in mutated keratin filaments, which may not be able to form
the cellular support infrastructures necessary for cell stability and
- The KRT5
gene is located on chromosome 12q12-q13
and don't forget chromosome 17q12-q21, home of KRT14.
- What does the gene product (protein) normally do in the unaltered
Under normal circumstances, the KRT5 and KRT14 genes code for keratin
5 and keratin 14, respectively.
Within the cell are 3 types of cytoskeletal elements: microtubules, thin
filaments (actin), and intermediate
filaments. These elements work together to provide the cell with structural
integrity, cell shape, and cell and organism motility.
Cells that undergo mechanical stress contain a lot of intermediate filaments,
which provide stability and durability to the cell. Of the 5 different
types of intermediate filaments, keratins comprise 2. These include the
basic and acidic keratins. Cells containing keratin are referred to as
Many keratins form copolymers. They dimerize in coiled-coil interactions.
Keratins 5 and 14 naturally partner together. The following picture illustrates
the formation of an intermediate filament from a single keratin monomer
(A) to a dimer (B) and its subsequent formation into an intermediate filament.
When you look at part B of the following figure, keratin 5 would be 1
of the partners in the coil and keratin 14 would be the other.
Keratin 5 and 14 are expressed in the basal layer of stratified epithelia.
The keratin networks formed by keratins 5 and 14 can comprise up to 25%
of the cell's content. The epidermis is the most notable epithelial tissue
affected by this disease, but the cornea and tongue also contain epithelial
tissue and thus could be affected by EB. In the following figure of the
skin, you can see the topmost layer of the skin is the epidermis. The
bottom-most, or basal, layer of the epidermis is where the keratin-containing
A second natural partner for keratin 5 is keratin 15. Keratin 15 is more
abundantly expressed in internal stratified squamous epithelium, like
- The genetic and molecular nature of the disease
EB is caused by a missense mutation in either of the KRT5 or KRT14 genes.
In the disease state, the keratins are unable to assemble properly due
to mutations in the keratin rod and thus are unable to form the cytoskeletal
infrastructure necessary for cell integrity. This infrastructure is also
absent if keratin 14 (a null mutation) is missing as this destabilizes
keratin 5. The mutation of KRT14 results in a single amino acid change
that causes the keratin to form fragile structures instead of normal bundles
of parallel rods.
Compare the following picture of mutated epidermis with the above picture
of normal epidermis.
The cells of people with EBS display clumps or aggregates of keratin filaments
in the cell cytoplasm. These clumps can exacerbate cell trauma.
The following image illustrates the cell in the disease state quite well.
It displays what a normal cell cytoskeleton ought to look like and what
happens in the disease states. The wavy blue lines in the cell in the
lower right corner are supposed to depict a blister.
from Elaine Fuchs, Don W. Cleveland. "A Structural Scaffolding of Intermediate
Filaments in Health and Disease". Science Magazine. Volume 279, Number
5350, Issue of 23 Jan 1998, p. 514.
Mutations at the ends of the keratin rod, which are highly conserved,
are especially deleterious. The more severe forms of EB oftentimes involve
an arginine to a cysteine or a histadine substitution, which is vital
for elongation of the keratin rod. The following figure indicates the
location of mutation on the keratin filament that produces specific EB
phenotypes. The hatched portions represent the highly conserved end regions.
Studying this diagram, you can correlate the mutation location on the
keratin filament with severity of EB. Weber-Cockayne is the mildest form
with delayed onset and blisters usually isolated to the hands and feet.
Koebner is more severe with generalized blistering with onset at birth
or sometimes later. Dowling-Meara is the severest form with blisters forming
in clusters with onset at birth.
The disease is usually first noticed due to recurrent and unusual blistering
or skin damage. The patient or parent notices unusual fragility of the skin
and will seek medical treatment and advice. The doctor will usually perform
a skin biopsy to determine what illness the patient has.
With a skin biopsy, the doctor will examine a sample of the patient's skin,
often from a fresh blister, and study it under a high-powered microscope to
determine where in the skin the structural defects are occurring. Also, the
skin sample will be examined using a monoclonal antibody stain that binds
to a protein found in the basal layer of the epidermis. Absence of staining
indicates absence of that protein. Once the disease and subtype is identified
and confirmed, further molecular studies may be performed to determine the
mode of inheritance and where the mutation is located. Learning the mode of
inheritance (autosomal dominant or recessive) is useful for parents for family
Prenatal testing is also available. This is performed by drawing a sample
of chorionic villi during the first trimester or amniotic fluid during the
second trimester. This sample is sent to a genetic testing laboratory to see
if the mutation exists in the fetus.
There is currently no cure for EB. Patients can only take certain preventative
and palliative measures to reduce the incidence of skin damage, such as careful
selection of clothing and maintaining moderate temperatures. Children with
this disorder may need to be bundled up in bandages (like the picture up at
top) to prevent or minimize injury.
The patient must take especial care when treating blisters or other open wounds
as infections are one of the main causes of death. In extreme circumstances,
surgery may be necessary to remove debilitating scar tissue, especially in
the esophagus, where damage can be extensive enough to require a feeding tube.
Thus far, the only treatment available is OrCel,
which is composite cultured skin manufactured by Ortec International Inc.
It has been approved by the FDA for humanitarian-use for the treatment of
chronic dermal ulcers such as those of an EB patient.
Apligraf, made by Novartis
is a similar product that has been approved for only for foot ulcers but may
have potential to also treat skin ulcers produced by EB.
- DebRA: Dystrophic Epidermolysis
Bullosa Research Association of America, Inc. This non-profit group is
dedicated to finding a cure for EB and offers information and support
services on its web site. This group is based in the U.S. and also has
a U.K. and international offices.
- Contact a Family:
This is a site based in the UK. It offers general information about EB
and contact information for a local liaison, who may be able to give specific
information about the support services near you.
- National Epidermolysis
- Family Village:
Great for finding EB chat rooms.
- EB Info World: This is a personal
web site assembled by a woman whose son suffers from a severe form of
EB. Content is posted to inform, to support, and to inspire other families
with this disorder. (If you are visiting this site, please be patient.
It may be a bit slow to load since it is not a "commercial" site.)
- EB Medical
Research Foundation: This foundation funds research to find cures
and treatments for EB. More information should be posted as research progresses.
- KUMC (Kansas
University Medical Center): Great for finding international-based resources.
Official Patient's Sourcebook on Epidermolysis Bullosa: A Revised and
Updated Directory for the Internet Age (link goes to Amazon)
- NCBI's Disease Database: N/A
- NCBI's OMIM: KRT5
- HGMD, Human Gene Mutation Database: KRT5
Organization for Rare Disorders (NORD)
- Coulombe PA, Hutton ME, Vassar R, Fuchs E. A function for keratins and
a common thread among different types of epidermolysis bullosa simplex
diseases. J Cell Biol. 1991 Dec;115(6):1661-74. Abstract
- Fuchs E, Cleveland DW. A structural scaffolding of intermediate filaments
in health and disease. Science. 1998 Jan 23;279(5350):514-9. Abstract
- Ma L, Yamada S, Wirtz D, Coulombe PA. A 'hot-spot' mutation alters the
mechanical properties of keratin filament networks. Nat Cell Biol. 2001
- Schuilenga-Hut PH, Vlies P, Jonkman MF, Waanders E, Buys CH, Scheffer
H. Mutation analysis of the entire keratin 5 and 14 genes in patients
with epidermolysis bullosa simplex and identification of novel mutations.
Hum Mutat. 2003 Apr;21(4):447.Abstract
- What is the normal function
of keratin 5 in the body?
- Why can the same disease be linked to 2 different chromosomes? (hint1)
- What is the reason for the ranges in severity of the disease? (hint)
"I give permission to allow Dr. Marrs to post this report on the web as an
assignment in an upcoming Biology class, with my name cited as the author"