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).

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

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

@ K2C5_HUMAN

@ K5

@ 58 kda cytokeratin

@ Keratin-5

@ keratin, type II cytoskeletal 5

@ KRT5A

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.

Prevalence

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.

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.

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.

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.

Treatments & Drugs (2/3)

Surgery

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.

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.

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 9^th week of gestation. Alternatively, amniotic fluid drawn after the 11^th 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. 

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.

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.