Definition     |     Genetic Basis     |     Diagnosing Disease     |     Disease Treatment     |     Support Groups     |     References

1. Title

   Epidermolysis Bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types

   DEFINITION Homo_sapiens keratin 5 (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber-Cockayne types) (KRT5), mRNA.
   
   ACCESSION NUMBER NM_000424

   
   
   

2. Introductory Paragraph

   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.




3. Genetic Basis For Disorder

   • 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 durability.
   • 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 state?
     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 keratinocytes.
     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 cells lie.
     A second natural partner for keratin 5 is keratin 15. Keratin 15 is more abundantly expressed in internal stratified squamous epithelium, like the esophagus.
     
     
   
   
   
   • 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.
     
     
     Figure 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.
   
   
   
   




4. Disease diagnosis, genetic screening, or metabolic tests for disease

   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 planning.
   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.




5. Disease treatment

   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.




6. Patient Support Groups

   • 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 Bullosa Registry
   • 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.
   • The Official Patient's Sourcebook on Epidermolysis Bullosa: A Revised and Updated Directory for the Internet Age (link goes to Amazon)




7. References

   • NCBI's LocusLink
   • NCBI's Disease Database: N/A
   • NCBI's OMIM: KRT5 and KRT14
     • Koebner type
     • Dowling-Meara type
     • Weber-Cockayne type
   • NCBI's PubMed
     Medline
   • HGMD, Human Gene Mutation Database: KRT5 and KRT14
   • National 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 May;3(5):503-6. Abstract
   • 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




8. Extra Credit Questions

   1. What is the normal function of keratin 5 in the body?
   2. Why can the same disease be linked to 2 different chromosomes? (hint1)     (hint2--go to Causes)
   3. What is the reason for the ranges in severity of the disease? (hint)




9. Length:

   1792 words




10. Name:

    Sheri Groen-Roberts
    "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"