Epidermolysis bullosa simplex (Epidermolysis bullosa simplex) - Genes KRT5, KRT14 or CELP.
Epidermolysis bullosa simplex belongs even group of genetic disorders called bullous epidermolysis that make the skin very fragile and easily off. Often, blisters and erosions on the skin occur in response to injury or lower friction as rubbing or scratching. Epidermolysis bullosa simplex is one of the main forms of epidermolysis bullosa. Signs and symptoms of this disease vary widely among affected individuals. Overall, blisters mainly affect the hands and feet in mild cases, and usually disappear without scarring. Severe cases of the disease include widespread blistering that can lead to infections, dehydration and other medical problems. Severe cases can be life - threatening in infancy.
They have identified four main types of epidermolysis bullosa simplex. Although the types differ in severity, characteristics overlap significantly and are caused by mutations in the same gene. The mildest form simple epidermolysis bullosa, known as the localized type (formerly called the Weber-Cockayne types), is characterized by blistering starting at any time between childhood and adulthood and usually limited to the skin of the hands and feet. Later, the skin may hyperkeratosis. For its part, the type of Dowling-Meara is the most severe form of epidermolysis bullosa simplex. Blisters may appear in groups and occur anywhere on the body, including inside the mouth. These blisters are present from birth and tend to improve with age. Affected individuals also have an abnormal nail growth and hyperkeratosis on the palms and soles. A third form of epidermolysis bullosa simplex, known as generalized other type (formerly called the Koebner), is associated with generalized blisters appear at birth or in early childhood. Blistering tends to be less severe than in the type of Dowling-Meara. Epidermolysis bullosa simplex with mottled pigmentation is characterized by patches of darker skin on the trunk, arms and legs that disappear in adulthood. This form of the disease also involves blistering of the skin from early childhood, hyperkeratosis of palms and soles, and abnormal nail growth.
In addition to the four main types described above, it has identified another skin disorder associated with epidermolysis bullosa simplex, called the Ogna type. This type of disease is due to mutations in a gene that is not associated with other types of epidermolysis bullosa simplex. It is unclear whether the Ogna type is a subtype of epidermolysis bullosa simplex or represents a separate form of the disease.
The four main types of epidermolysis bullosa simplex are due to mutations in genes KRT5 or KRT14. Mutations in the CELP gene have been associated with type Ogna epidermolysis bullosa simplex.
The KRT5 genes located on the long arm of chromosome 12 (12q13.13) and KRT14, located on the long arm of chromosome 17 (17q21.2), encode proteins called keratin 5 and keratin 14, respectively. Keratins are a group of tough and fibrous proteins that form the structural framework of certain cells, particularly cells that form the skin, hair and nails. These proteins act together to provide strength and elasticity to the skin. It is believed that keratin 5 may also play a role in the transport of melanosomes, important for pigmentation. Meanwhile, it is believed that keratin 14 may also play a role in the formation of sweat glands and the development of fingerprints on the skin of the hands and feet.
There are more than 100 mutations in the gene KRT5 and more than 60 mutations in the KRT14 gene in people with epidermolysis bullosa simplex. Most of these mutations alter amino acids used in encoding keratins. The most severe form of epidermolysis bullosa simplex, type of Dowling-Meara, usually caused by changes in the regions of keratin which are essential for the assembly of keratin intermediate filaments. Milder forms of the disease, including localized type (formerly called the Weber-Cockayne types) and a form known as generalized other type (formerly called the Koebner) are often caused by changes affecting regions less critical protein. Mutations that cause severe forms of the disease seriously alter the assembly of keratin intermediate filaments, whereas mutations that result in milder forms harm the set of keratin filaments to a lesser degree. Another form of the disease called epidermis bullosa simplex mottled pigmentation is typically due to a mutation that replaces the amino acid proline with leucine at amino acid position 25 of the protein (Pro25Leu or P25L).
The CELP gene, located on the long arm of chromosome 8 (8q24), encodes a protein called plectin. This protein is encoded in many different tissues in the body, including skin and muscle. Within cells, plectin interacts with various molecules that make up the cytoskeleton. For example, plectin interacts with the intermediate filaments, which form networks that provide support and strength to the cells. The exact function of plectin in different tissues is unclear. In skin cells, this protein is an essential part of the hemidesmosomes, connecting the intermediate filament network to the cell membrane. It is also a component of the desmosomal junctions forming between neighboring cells. As part of these structures, plectin plays a critical role in anchoring of the epidermis to the underlying layers.
It has identified at least one mutation in the CELP gene is associated with the characteristics of epidermolysis bullosa simplex. This mutation was found in a small number of families with one form of the disease known as the Ogna type. It is unclear whether this rare disorder is actually a subtype of epidermolysis bullosa simplex or represents a separate form of the disease. The mutation responsible for Ogna type replaces the amino acid arginine with tryptophan amino acid at position 2000 of the protein (Arg2000Trp or R2000W). It is believed that this mutation may change how the protein folds, making a three-dimensional shape, which may prevent interaction with the molecules forming the cytoskeleton. In the skin, these changes make epidermal cells become fragile and easily damaged. As a result, the skin is less resistant to friction and minor trauma.
In general, the disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to result in the alteration. Some affected people inherit the mutation from an affected parent. Other cases are caused by new mutations in the gene and occur in people with no history of disease in your family. In rare cases, the disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with epidermolysis bullosa simplex, by complete PCR amplification of the exons of KRT5, KRT14 yPLEC, respectively, and subsequent sequencing genes.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).