Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Erythrokeratodermia variabilis et progressiva - GJB3GJB4, GJA1 and KRT83 genes 

Erythrokeratodermia variabilis et progressiva (EKVP), also known as Darier-Gottron syndrome, is an alteration of the skin that is either present at birth, or becomes evident in childhood. Although its signs and symptoms vary, it is characterized by two main features: hyperkeratosis and the presence of erythematous areas. Hyperkeratosis involves thickened areas in the skin that are usually reddish brown, and that can be found in many parts of the body or develop only in a small area. Hyperkeratosis does not usually disappear, the affected areas may vary in size and shape, and in some affected people they get larger over time, until they stabilize. The areas of thickened skin occur in the same places on both right and left sides of the body. The second important feature of EKVP is the presence of erythematous areas, which, unlike hyperkeratosis, are usually transient. These areas vary in size, shape and location, and can develop anywhere in the body. The redness can be activated by sudden changes in temperature, emotional stress, trauma or irritation of the area. Usually, the erythema disappears in a matter of hours to days.

This process may be due to mutations in the GJB3 (gap junction protein beta 3), GJB4 (gap junction protein beta 4), GJA1 (gap junction protein alpha 1) and KRT83 (keratin 83) genes.

The GJB3 and GJB4 genes, located on the short arm of chromosome 1 (1p34.3), as well as the GJA1 gene, located on the long arm of chromosome 6 (6q22.31), encode the connective proteins 31, 30.3 and 43, respectively. These proteins are part of the connexin family, a group of proteins that form channels on the cell surface called Gap junctions. Gap-type intercellular junctions open and close to regulate the flow of nutrients, ions and other signaling molecules from one cell to another. They are essential for direct communication between neighboring cells. Gap junctions formed with connexins 31, 30.3 and 43 are found in several tissues, including the epidermis.           

At least 15 mutations in the GJB3 gene and 8 mutations in the GJB4 gene associated with erythrokeratodermia variabilis et progressiva (EKVP) have been identified. These genetic changes alter the structure of connexins encoded from these genes. Studies suggest that abnormal proteins can accumulate in the endoplasmic reticulum (ER), triggering a harmful process known as ER stress (endoplasmic reticulum stress). ER stress is likely to damage and cause premature death of epidermis cells, which appears to be the basis for the development of erythematous areas.

At least two mutations in the GJA1 gene have been described in individuals with EKVP, each of whom changes a single amino acid in connexin protein 43. These changes result in the synthesis of an abnormal version of the protein that cannot reach cell surface and is retained in the Golgi apparatus. However, it is unknown how a deficiency of connexin 43 on the cell surface affects the structure of the junctions in the epidermis, or how these changes give rise to the skin abnormalities characteristic of the EKVP.

The KRT83 gene, located on the long arm of chromosome 12 (12q13.13), encodes the K83 protein of type II hair keratin. Each keratin protein is associated with another keratin protein to form intermediate filaments. These filaments constitute robust networks that provide strength and resistance to tissues and protect them from damage caused by daily physical stress. The K83 protein is found in the cells that make up the inner compartment of the hair shaft, where it helps give the hair its strength and elasticity.

Usually, EKVP is inherited with an autosomal dominant pattern, which means that a copy of an altered gene in each cell is sufficient to express the disease. In most cases, an affected person inherits the mutation from an affected parent. Other cases are due to new genetic mutations and occur in people with no history of the disease in their family. Some studies have suggested that EKVP may also have an autosomal recessive inheritance pattern. However, this inheritance pattern has only been described in a small number of affected families, and not all researchers agree that it is autosomal recessive. Autosomal recessive inheritance 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. In rare cases, the mutation is found in some of the body's cells, but not in others. In these individuals, the disease is described as EKVP in mosaic or inflammatory linear verrucous epidermal nevus (ILVEN). In mosaic EKVP, characteristic skin abnormalities affect a small region of the organism, and generally occur on only one side, and can also follow a skin pattern known as Blaschko lines.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with erythrokeratodermia variabilis et progressiva (EKVP), by means of the complete PCR amplification of the exons of the GJB3, GJB4, GJA1 and KRT83 genes, and their subsequent sequencing.

Recommended samples non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).