Junctional epidermolysis bullosa – COL17A1, LAMA3LAMB3, LAMC2 and ITGB4 genes

Juntional epidermolysis bullosa (JEB) is a genetic process that leads to the development of fragile skin and a tendency to blister and erosion in response to minor injuries or friction. Two main types of juntional epidermolysis bullosa of variable severity have been described: the severe generalized form and the intermediate generalized form. The characteristics of both types overlap significantly and can be caused by mutations in the same genes.

The most severe form is manifested from birth or early childhood and is characterized by the development of blisters in large regions, which can even affect the mucous membranes. The blisters result in the formation of scars and granulation tissue, which can cause serious infections and loss of proteins, minerals and liquids. In addition, granulation tissue in the airways can cause difficulty breathing. Other signs of the severe form may include fusion of the fingers and toes, abnormalities of the nails and feet, contractures, alopecia and thinning of the tooth enamel. Due to the severity of these symptoms, newborns with this condition generally do not survive beyond the first year of life.

The mildest form of the disease, known as the intermediate form, can be limited to the hands, feet, knees and elbows, and often improves after the neonatal period. Other characteristic features of the intermediate form include hair loss, abnormal toenails and irregular tooth enamel. Most affected people do not have extensive scarring or granulation tissue formation, so respiratory difficulties and other serious complications are rare.

This process is due to mutations in the LAMB3 (laminin subunit beta 3), LAMA3 (laminin subunit alpha 3), LAMC2 (laminin subunit gamma 2), COL17A1 (collagen type XVII alpha 1 chain) and ITGB4 (integrin subunit beta 4) genes. LAMB3 gene mutations are responsible for approximately 70 percent of all cases of unilateral epidermolysis bullosa (JEB).

The LAMB3 (1q32.2), LAMA3 (18q11.2) and LAMC2 (1q25.3) genes each encode a subunit of the 332 laminin protein. This protein plays an important role in strengthening and stabilizing the skin by helping to bind the epidermis to the underlying layers. At least 100 mutations in the LAMB3 gene, 50 mutations in the LAMA3 gene and more than 40 mutations in the LAMC2 gene have been identified that lead to the development of both the intermediate and severe form of unilateral epidermolysis bullosa. Mutations in any of the three genes of laminin 332 result in the synthesis of a defective or non-functional version of this protein. Without functional laminin 332, the cells in the epidermis are fragile and easily damaged. Friction or other minor trauma can cause the skin layers to separate, leading to blistering.

The COL17A1 gene, located on the long arm of chromosome 10 (10q25.1), encodes a protein that is used to constitute type XVII collagen. Type XVII collagen helps to bind the epidermis to the underlying layers of the skin, making the skin strong and flexible. More than 100 mutations in the COL17A1 gene have been identified in people with epidermolysis bullous junction (JEB), most of which add or remove several nucleotides in the COL17A1 gene or create a premature stop signal in the instructions to make the chain pro-α1 (XVII). These changes reduce the amount of functional collagen type XVII in the skin. Without enough collagen, the epidermis is weakly attached to the underlying layers of the skin, so friction or other minor traumas can cause the layers of the skin to separate, leading to the formation of blisters. Most mutations of the COL17A1 gene cause the intermediate form; However, some people with mutations in the COL17A1 gene have developed the most severe form.

This disease is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Juntional epidermolysis bullosa (JEB), by means of complete PCR amplification of the exons of the COL17A1, LAMA3, LAMB3, LAMC2 and ITGB4 genes, respectively, and their subsequent sequencing.

Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).