Tuesday, December 25, 2012

KRT5 Gene : Function

Function of the KRT5 gene...

The KRT5 gene provides instructions for making a protein called keratin 5.

Keratins are a group of tough, fibrous proteins which form the structural framework for the cells which make up the skin, hair, and nails. Keratin 5 is produced in cells called keratinocytes found in the outer layer of the skin (the epidermis).

Keratin 5 partners with a similar protein, keratin 14, to form molecules called keratin intermediate filaments. These filaments assemble into strong networks which help keratinocytes to attach together and anchor the epidermis to underlying layers of skin. The network of keratin intermediate filaments provides strength and resilience to the skin and protects it from being damaged by friction and other everyday physical stresses.

Researchers also believe that keratin 5 may also play a role in transporting ‘melanosomes’, which are cellular structures that produce a pigment called melanin. The transport of these structures into keratinocytes is important for normal skin coloration (pigmentation).

Monday, December 24, 2012

KRT5 Gene : Gene Family

The Gene Family…

The KRT5 gene belongs to a family of genes called KRT (keratins).ë

ëA gene family is a group of genes which share important characteristics

Sunday, December 23, 2012

KRT5 Gene : The Name

The official name of the KRT5 Gene…

Official Name of KRT5 gene is ‘keratin 5’.

Official Symbol: KRT5 is the gene's official symbol. 

Other Names used for the KRT5 gene or gene products…
@ CK5
@ cytokeratin 5
@ EBS2
@ K5
@ 58 kda cytokeratin
@ Keratin-5
@ keratin, type II cytoskeletal 5

Saturday, December 22, 2012

The Gene...

Genes related to Epidermolysis Bullosa Simplex [EBS]...

Mutations in the KRT5 and KRT14 genes are responsible for the 4 major types of Epidermolysis Bullosa Simplex. These genes provide instructions for making proteins ‘keratin 5’ and ‘keratin 14’. These tough, fibrous proteins work together to provide strength and resiliency to the outer layer of the skin (the epidermis).

Mutations in either the KRT5 or KRT14 gene make the epidermis cells fragile and easily damageable. As a result, the skin becomes less resistant to friction & minor trauma and blisters easily.

In rare cases of EBS, no mutation in the KRT5 or KRT14 have been identified. Mutations in another gene, PLEC, have been associated with the uncommon Ogna type of the condition. The PLEC gene provides instructions for making a protein called plectin, which helps the epidermis to attach with the underlying layers of skin. Researchers continue to search for PLEC gene mutations in people with epidermolysis bullosa simplex. They are also working to determine how these mutations lead to the major features of the condition.

Monday, December 17, 2012


How common is Epidermolysis Bullosa Simplex?

The exact prevalence of epidermolysis bullosa simplex is unknown, but it is estimated that EBS affect 1 in 30,000 50,000 people. The Weber-Cockayne type is the most common form of EBS.

Sunday, December 16, 2012

Genetics .....[EBS]

Epidermolysis Bullosa Simplex [EBS]

We already discussed the basic and the symptoms for Epidermolysis Bullosa Simplex [EBS]. Now let’s take a look in details on the genetic patterns and possible mutational analysis.

Researchers have identified 4 major types of EBS. Although the types differ in severity, their features overlap significantly and they are caused by mutations in the same genes.

The mildest form of EBS, known as the Weber-Cockayne type is characterized by skin blistering mainly in hands and feet which begins anytime between childhood and adulthood. Later in life, skin on the palms and soles of the feet may thicken and harden (hyperkeratosis).

In the Koebner type blisters appear at birth or in early infancy and are more widespread.

Another form of the disorder epidermolysis bullosa simplex with mottled pigmentation, is characterized by patches of darker skin on the trunk, arms and legs which fade in adulthood — this form of the disorder also involves skin blistering from early infancy, hyperkeratosis of the palms and soles and abnormal nail growth.

The Dowling-Meara type is the most severe form of epidermolysis bullosa simplex. Extensive, severe blistering can occur anywhere on the body, including the inside of the mouth and in clusters. Blisters are present from birth and tends to improve with age. Affected individuals also experience abnormal nail growth and hyperkeratosis of the palms and soles.

Researchers have identified another skin condition characteristic of epidermolysis bullosa simplex Ogna type it is caused by mutations in a gene that is not associated with the other types of epidermolysis bullosa simplex. Researchers are still not sure whether Ogna type is a subtype of epidermolysis bullosa simplex or represents a separate form of epidermolysis bullosa.

Friday, December 7, 2012

Lifestyle & Home Remedies

Careful wound care and good nutrition are essential patient’s health. If blisters are left intact, they can enlarge, which creates a bigger wound when they finally break. Safe ways should be followed for breaking and drain blisters before they get too large. Doctors can also recommend products to use to keep the affected areas moist to promote healing, such as gauze that contains a moisturizing agent, and prevent infection.
When tending patient’s wounds:
  • Always wash hands before touching patient’s blisters.
  • If a soiled dressing sticks, don't pull it off. Soak the area in warm water until the dressing loosens.
If oral or ‘esophageal’ blisters are inhibiting patient’s ability to eat, here are some suggestions:
  • If drinking from breast or bottle causes an infant to develop blisters, try using nipples designed for premature infants or infants with cleft palate or a facial birth defect, or use a syringe or eyedropper.
  • For older children, puree foods with extra liquid such as broth or milk to make them softer.
  • Serve soft, nutritious foods such as vegetable soups and fruit smoothies.

Thursday, December 6, 2012

Treatments & Drugs (3/3)

Physical Therapy
Working with a physical therapist can help ease the limitations on motion caused by scarring and shortening of the skin (contracture). Swimming may be helpful for many people.
Intensive studies are under way to find better ways to treat and relieve the symptoms of Epidermolysis Bullosa, including gene replacement, bone marrow transplantation and recombinant protein therapies.

Wednesday, December 5, 2012

Treatments & Drugs (2/3)

Ideally, deformities and fusion of the hands and feet can be prevented with daily protective wrapping. However, repeated blistering and scarring can cause deformities such as fusing of the fingers or toes or abnormal bends in the joints (contractures). Doctors may recommend surgery to correct these deformities especially if they interfere with normal motion.
Blistering and scarring of the ‘esophagus’ may lead to esophageal narrowing, making eating difficult. Surgery to widen (dilate) the esophagus may be needed. Using light sedation, the surgeon positions a small balloon in the esophagus and inflates it to dilate the area.
To improve nutrition and help with weight gain, a tube (gastrostomy tube) may be implanted to deliver food directly to the stomach. Feedings through the tube may be delivered overnight using a pump. Eating through the mouth is continued if possible so that the child will be able to eat with others for normal socializing.

Tuesday, December 4, 2012

Treatments & Drugs (1/3)

Treatment of Epidermolysis Bullosa aims mainly at preventing complications and easing discomfort from blistering.

Skin care

Blisters may be large and, once broken, susceptible to infection and fluid loss. Following tips are recommend for treating blisters and raw skin:
c  Puncture blisters with a sterile needle to prevent the blister from spreading further. Leaving the roof of the blister intact allows for drainage of the blister while protecting the underlying skin.
c  Apply antibiotic ointment, petroleum jelly or other moisturizing substance before applying a special non-sticking bandage.
c  Soak wounds with a disinfectant solution. For wounds which doesn't heal may cause infection with bacteria such as pseudomonas. Soaks with diluted vinegar solution are sometimes used as a disinfectant, starting with a low enough concentration that the solution doesn't sting but is still helpful to remove germs.

Monday, December 3, 2012

Diagnosis (3/3)

Prenatal diagnosis 

Once an Epidermolysis Bullosa (EB) diagnosis has been confirmed by skin biopsy and molecular genetic studies (DNA analysis) prenatal diagnosis of future pregnancies becomes possible. DNA for prenatal diagnosis can be obtained as a chorionic villi sample as early as the 9th week of gestation. Alternatively, amniotic fluid drawn after the 11th week can provide the necessary DNA.
Following steps are required for prenatal diagnosis of EB:
1.    Biopsy diagnosis of an affected family member is needed to identify EB subtype.
2.    After subtype is identified, DNA sample is sent to lab for identification of the genetic mutation.
3.    After genetic mutation is identified, amniotic fluid or chorionic villus sampling (CVS) is obtained during pregnancy which is sent to the genetic laboratory and evaluated for the previously identified mutation. Placental cells may be obtained through a CVS, performed at approximately 10-12 weeks gestation, and amniotic fluid may be obtained through amniocentesis, at approximately 15-18 weeks gestation.
Many EB parents prefer to have prenatal diagnosis completed utilizing CVS rather than amniocentesis.
Preimplantation genetic diagnosis (PGD) improves the likelihood of an EB-free birth. PGD is accomplished by genetic analysis of a fertilized egg before implantation with the following step:
1.    DNA analysis is performed to identify the genetic mutation present in the affected person.
2.    Hormone injections to the prospective mother to stimulate her ovaries for development of eggs.
3.    The eggs are retrieved from the mother and fertilized with the father’s sperm, usually by a reproductive endocrinology (in vitro fertilization).
4.    When the fertilized egg has developed into at least eight cells, one cell is removed and analyzed in the laboratory to determine whether it carries the genetic mutation present in the affected person.
5.    If the mutation is not detected, the fertilized eggs are implanted in the mother’s womb in anticipation of the birth of a child who does not have EB.

This procedure has resulted in successful outcomes for many EB families but it is expensive. 

Sunday, December 2, 2012

Diagnosis (2/3)

DNA Mutation Analysis

Based on the results of the skin biopsy, genetic testing may be performed to confirm the specific gene and DNA mutation(s) present.
Molecular genetic studies (DNA analysis) are done after the sub-type of Epidermolysis Bullosa (EB) has been confirmed by skin biopsy. Molecular studies are done to identify the specific genetic mutation and to determine the mode of inheritance (recessive vs. dominant). This information is helpful for family planning and makes prenatal diagnosis of subsequent pregnancies possible.
After immunoflurescent microscopy DNA mutational analysis is the final step in elucidating the underlying molecular defect, and in most cases, it reduces the number of genes to be screened. DNA is extracted from blood of the patient and family members. Initial mutation screening is performed by restriction fragment-length polymorphism analysis, hotspot analysis, and finally, direct DNA sequencing.
But in a small number of people, DNA mutation analysis is unable to identify the specific mutations that are suspected to be present based on the results of the skin biopsy.

Saturday, December 1, 2012

Diagnosis (1/3)

Doctor may suspect Epidermolysis Bullosa (EB) from the appearance of the skin but the following tests are needed to confirm the diagnosis

Skin Biopsy

When EB is suspected, a skin biopsy should be taken to confirm the diagnosis and identification of type of EB. The skin biopsy must be taken from a new blister. This is best performed on an area of skin where the physician has tried to induce a blister by rubbing the skin with a pencil eraser back & forth until epidermal separation is appreciated.

To perform the skin biopsy, the physician will use an anesthetic to first numb an area of skin. Then, the physician will take a small sample of skin from the edge of the blister for examination. Sometimes, 2 smaller samples may require to be taken. The skin samples must be processed for specific studies, immunofluorescence antigen (IFA) mapping and transmission electron microscopy (EM).

Immunofluorescence antigen mapping is performed to identify exactly where the blister has occurred and which proteins are involved (absent/diminished in amount). This is a specialized study which is generally done by a pathologist in a laboratory that specializes in this procedure.

Friday, November 30, 2012

Cause (5/5)

Anchoring fibrils

Type VII collagen is the primary component of anchoring fibrils. Type VII collagen contains a large N-terminal globular domain (NC-1), which interacts with laminin 5 in the lamina densa; a long collagenous domain; and a smaller C-terminal globular domain (NC-2), which is cleaved proteolytically during anchoring fibril formation. Type VII collagen chains form a triple helix and 2 molecules join together in an antiparallel fashion in the next step. Next, anchoring fibrils are formed by lateral associations of antiparallel dimers. Anchoring fibrils wind around the dermal interstitial collagen fibrils and reinsert back upon the lamina densa, attaching the BMZ to the underlying dermis.

Thursday, November 29, 2012

Cause (4/5)

Anchoring filaments

These structures contain the extracellular portions of collagen XVII (BP180) and alpha-6-beta-4 (α-6-β-4) integrin. In addition, anchoring filaments contain the molecules ‘laminin 5and laminin 6’. Similar to all members of the family of laminin proteins, laminin 5 is a large heterotrimeric molecule, containing α-3, β-3, and g-2 chains. Laminin 5 forms a disulfide-bonded attachment to laminin 6, the other known anchoring filament laminin, which contains α-3, β-1, and g-1 chains. Laminin 5 also forms a strong association with type VII collagen, which serves to connect anchoring filaments with anchoring fibrils.

Wednesday, November 28, 2012

Cause (3/5)


The structure of ‘Hemidesmosomes’ contain intracellular proteins including ‘plectin’ and ‘BP230.

Plectin (HD1) is a 500-kd protein which binds intermediate filaments.

BP230 (also termed as BPAG1) is a 230-kd protein which has homology to both desmoplakin and plectin. BP230, like plectin, functions in the connection between ‘hemidesmosomes’ and ‘intermediate filaments’.

Hemidesmosomes also contain the intracellular portions of the transmembrane proteins collagen XVII (BP180) and alpha-6-beta-4 (α-6-β-4) integrin. The β-4 integrin subunit performs a central role in hemidesmosome formation and contains an especially large cytoplasmic domain, which interacts with other proteins of the hemidesmosomal plaque. Collagen XVII is a transmembrane collagenous protein which interacts with α-4 integrin and BP230 intracellularly and with laminin 5 extracellularly.

Monday, October 29, 2012

Cause (2/5).....

Keratin Filaments

Keratins 5 and 14 combine to form intermediate filaments in basal keratinocytes. Keratins contain a central alpha-helical rod with several nonhelical interruptions, as well as nonhelical carboxyterminal and aminoterminal regions. The regions of highest conservation between the keratins are located on the ends of the keratin rod in the helix boundary motifs. Keratin intermediate filaments insert upon electron-dense structures termed hemidesmosomes.

Sunday, October 28, 2012

Cause (1/5)....

Basement Membrane Zone (BMZ)

Many stratified squamous epithelial tissues, such as the skin and oral mucosa, contain a complex Basement Membrane Zone (BMZ). The BMZ is composed of many specialized components which combine to form anchoring complexes.

 At the superior aspect of the BMZ, keratin-containing intermediate filaments of the basal cell cytoskeleton insert on basal cell plasma membrane condensations termed ‘hemidesmosomes’. Anchoring filaments extend from the basal cell plasma membrane into the extracellular environment and span the lamina lucida, connecting hemidesmosomes with the lamina densa.

At the most inferior aspect of the BMZ, type VII collagen-containing anchoring fibrils extend from the lamina densa into the papillary dermis connecting the lamina densa to anchoring plaques, trapping interstitial collagen fibrils. Thus, the cutaneous BMZ connects the extensive basal cell cytoskeletal network with the abundant network of interstitial collagen fibrils in the dermis.

Saturday, October 27, 2012

Type/Epidermolysis Bullosa Acquisita (EBA)

Epidermolysis Bullosa Acquisita (EBA)

Epidermolysis Bullosa Acquisita (EBA) is another rare type of Epidermolysis Bullosa, which isn't inherited. Blistering associated with this condition occurs as the result of the immune system mistakenly attacking healthy tissue. It is similar to a condition called ‘bullous pemphigoid’, which also is related to an immune system disorder. EBA has been associated with Crohn's disease, an inflammatory bowel disease.

Friday, October 26, 2012

Type/Dystrophic Epidermolysis Bullosa (DEB)

Dystrophic Epidermolysis Bullosa (DEB)

Dystrophic Epidermolysis Bullosa (DEB)~ whose subtypes range from mild to severe, generally becomes apparent at birth or during early childhood. In Dystrophic Epidermolysis Bullosa (DEB), the mutation is involved in the production of a type of collagen, a strong protein in the fibers that hold the deepest, toughest layer of your skin together. As a result, the fibers are either missing or non-functional. DEB can be either dominant or recessive.
This is a group of diseases caused by defects of anchoring fibrils. Blisters heal followed by dystrophic scarring. Formation of milia (1- to 4-mm white papules) results as a consequence of damage to hair follicles.

Dominantly inherited dystrophic epidermolysis bullosa

The onset of disease usually is at birth or during infancy, with generalized blistering as a common presentation. With increasing age, an evolution to localized blistering is present. A common variant described by Cockayne-Touraine has an acral distribution and minimal oral or tooth involvement. Another variant described by Pasini features more extensive blistering, scarlike papules on the trunk (termed albopapuloid lesions), and involvement of the oral mucosa and teeth. Dystrophic or absent nails are common in both of these dominantly inherited dystrophic epidermolysis bullosa variants.

Recessively inherited epidermolysis bullosa

This group of diseases ranges from mild to severe in presentation.
A localized form, termed recessively inherited epidermolysis bullosa mitis, often involves acral areas and nails but shows little mucosal involvement. This subtype also demonstrates clinical manifestations similar to the dominantly inherited forms of dystrophic epidermolysis bullosa.
Severe recessively inherited epidermolysis bullosa, as described by Hallopeau-Siemens, usually shows generalized blistering at birth and subsequent extensive dystrophic scarring that is most prominent on the acral surfaces. This can produce pseudosyndactyly (mitten-hand deformity) of the hands and feet. Flexion contractures of the extremities are increasingly common with age. Nails and teeth also are affected. Involvement of internal mucosa can result in esophageal strictures and webs, urethral and anal stenosis, phimosis, and corneal scarring. Malabsorption commonly results in a mixed anemia resulting from a lack of iron absorption, and overall malnutrition may cause failure to thrive. Patients with severe recessively inherited epidermolysis bullosa who survive to childhood are at significant risk of developing aggressive SCC in areas of chronic erosions.

Recessively inherited dystrophic epidermolysis bullosa pseudosyndactyly (mitten-hand deformity) of the hands and feet
Ectodermal dysplasia-skin fragility syndrome is a rare disorder characterized by skin erosions, skin fragility and peeling beginning at birth or infancy that may be accompanied by alopecia, palmoplantar keratoderma, painful fissures, and nail dystrophy. Failure to thrive, cheilitis, hypohidrosis, and pruritus are other potential complications. The underlying molecular defect has been shown to be loss of function of the desmosomal protein plakophillin1. Plakophillin is expressed mainly in suprabasilar keratinocytes and outer root sheath cells. Microscopic findings in this disease usually show intraepidermal acantholysis, located in the areas where plakophillin 1 is normally expressed. The molecular defect involves loss of function mutations in the PKP1 gene coding for plakophillin 1.

Thursday, October 25, 2012

Type/Junctional Epidermolysis Bullosa (JEB)

Junctional Epidermolysis Bullosa (JEB)

Junctional Epidermolysis Bullosa (JEB) is usually severe type of the disorder generally becomes apparent at birth. In Junctional Epidermolysis Bullosa (JEB), the mutated genes are involved in the formation of thread-like fibers (hemidesmosomes) whic attach the epidermis to the basement membrane. This gene defect causes tissue separation and blistering in the basement membrane zone (BMZ).
Junctional Epidermolysis Bullosa (JEB) has autosomal recessive inheritance pattern in which both parents carrying one copy of the diseased gene and passing on the mutated gene, although neither parent may clinically have the disorder (silent mutation).
If both parents carry one faulty gene, there's a 25% chance each of their offspring will inherit two mutated genes — one from each parent — and develop the disorder.
Primary subtypes include a lethal subtype termed Herlitz or junctional epidermolysis bullosa letalis, a nonlethal subtype termed junctional epidermolysis bullosa mitis and a generalized benign type termed generalized atrophic benign epidermolysis bullosa.

Lethal junctional epidermolysis bullosa

The Herlitz or letalis form of junctional epidermolysis bullosa is characterized by generalized blistering at birth and arises from an absence or a severe defect in expression of the anchoring filament glycoprotein laminin 5. Patients with lethal forms of junctional epidermolysis bullosa show characteristic periorificial erosions around the mouth, eyes and nares, often accompanied by significant hypertrophic granulation tissue. Multisystemic involvement of the corneal, conjunctival, tracheobronchial, oral, pharyngeal, esophageal, rectal, and genitourinary mucosae is present. Internal complications of the disease include a hoarse cry, cough, and other respiratory difficulties. Patients with Herlitz junctional epidermolysis bullosa are at increased risk for death from sepsis or other complications secondary to the profound epithelial disadhesion and usually they do not survive past infancy.

 Junctional epidermolysis bullosa, Herlitz subtype.
This severe disease is characterized by generalized intralamina lucida blistering at birth, significant internal involvement, and a poor prognosis.

 Nonlethal junctional epidermolysis bullosa

Patients with junctional epidermolysis bullosa manifesting generalized blistering who survive infancy and clinically improve with age have junctional epidermolysis bullosa mitis. Usually, these patients do not present with the same type of hoarse cry or other significant respiratory symptoms as do patients with the Herlitz form. Instead, scalp, nail, and tooth abnormalities increasingly may become apparent. Periorificial erosions and hypertrophic granulation tissue can be present. Mucous membranes often are affected by erosions, resulting in strictures. Some patients with junctional epidermolysis bullosa mitis can present with blistering localized to the intertriginous regions.

Generalized atrophic benign epidermolysis bullosa

This is a relatively mild subtype characterized by generalized cutaneous blistering and presenting at birth. Blistering activity is worsened by increased ambient temperature, and blisters heal with a distinctive atrophic appearance. Extracutaneous involvement is rare, with the exception of teeth. Hypoplastic enamel formation results in significant tooth decay. Nail dystrophies and alopecia are other common clinical manifestations. Individuals with generalized atrophic benign epidermolysis bullosa have the potential to bear children and have a typical life expectancy. It should be noted that generalized atrophic benign epidermolysis bullosa is lumped together with nonlethal junctional epidermolysis bullosa in the newest epidermolysis bullosa classification consensus; however, it is clear that these 2 diseases are quite distinct clinically.

Wednesday, October 24, 2012

Type/ Epidermolysis Bullosa Simplex (EBS)

Before we move into more details of the genetic of each type & sub-type of Epidermolysis Bullosa (EB) let’s take a brief idea about each type.

 Epidermolysis Bullosa Simplex (EBS)

Epidermolysis Bullosa Simplex (EBS) is the most common and generally mildest form usually begins at birth or during early infancy. EBS is a collection of keratin disorders characterized by intraepidermal blistering with relatively mild internal involvement. Lesions typically heal without scarring. In EBS, mainly the palms of hands and soles of feet are affected. In EBS, the mutated genes are those involved in the production of keratin, a fibrous protein in the top layer of skin. The condition causes the skin to split in the epidermis, which produces blisters, usually scar formation.
Epidermolysis Bullosa Simplex (EBS) is inherited as autosomal dominant pattern. As we discussed earlier for EBS one single mutated gene from any of the parents is enough to develop the symptoms. However, if the parental condition is mild, there is a chance that EBS may not be diagnosed.
Occasionally, EBS may be the first in one’s family to be affected. In these cases, the mutation will have occurred in the womb before the child was born ~ neither of the parents carries the mutation and the child has a new mutation.
After that if EBS first generation go onto have children, they will have a 50% chance of developing Epidermolysis Bullosa Simplex (EBS).
The more severe Epidermolysis Bullosa Simplex (EBS) subtypes include Koebner, Dowling-Meara, and Weber-Cockayne forms.

Mild Epidermolysis Bullosa Simplex

Weber-Cockayne subtype is the most common form of Epidermolysis Bullosa Simplex (EBS). Blisters usually are precipitated by a clearly identified traumatic event. They can be mild to severe and most frequently occur on the palms and soles. ‘Hyperhidrosis’ can accompany this disorder.

Epidermolysis Bullosa Simplex, Weber-Cockayne subtype.
This mild bullous disease is characterized by localized blistering at sites of trauma such as the feet.

Severe Epidermolysis Bullosa Simplex

Usually, a generalized onset of blisters occurs at or shortly after birth. Hands, feet, and extremities are the most common sites of involvement. Palmoplantar hyperkeratosis and erosions are common, especially in Koebner epidermolysis bullosa simplex.
Dowling-Meara epidermolysis bullosa simplex involves more oral mucosa and manifests with grouped herpetiform blisters (hence the term epidermolysis bullosa simplex herpetiformis).

Epidermolysis Bullosa Simplex, Koebner subtype.

Palmoplantar blistering and hyperkeratosis are noted.

Epidermolysis Bullosa Simplex, Koebner subtype.
Close-up image shows hyperkeratotic papules and plaques on the palm.