Erythrokeratodermia variabilis et progressiva (EKVP) is a skin disorder that is present at birth or becomes apparent in infancy. Although its signs and symptoms vary, the condition is characterized by two major features. The first is hyperkeratosis, which is rough, thickened skin. These patches are usually reddish-brown and can either affect many parts of the body or occur in only a small area. They tend to be fixed, meaning they rarely spread or go away. However, the patches can vary in size and shape, and in some affected people they get larger over time. The areas of hyperkeratosis are generally symmetric, which means they occur in the same places on the right and left sides of the body.

The second major feature of EKVP is patches of reddened skin called erythematous areas. Unlike the hyperkeratosis that occurs in this disorder, the erythematous areas are usually transient, which means they come and go. They vary in size, shape, and location, and can occur anywhere on the body. The redness is more common in childhood and can be triggered by sudden changes in temperature, emotional stress, or trauma or irritation to the area. It usually fades within hours to days.

EKVP can be caused by mutations in several genes, including GJB3, GJB4, and GJA1. These three genes provide instructions for making proteins called connexins 31, 30.3, and 43, respectively. These proteins are part of the connexin family, a group of proteins that form channels called gap junctions on the surface of cells. Gap junctions open and close to regulate the flow of nutrients, charged atoms (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 outermost layer of skin (the epidermis).

The GJB3, GJB4, and GJA1 gene mutations that lead to EKVP alter the structure or location of the connexins produced from these genes. Some GJB3 or GJB4 gene mutations lead to the production of abnormal connexins that can build up in a cell structure called the endoplasmic reticulum (ER), triggering a harmful process known as ER stress. Researchers suspect that ER stress damages cells in the epidermis and leads to their premature death. Other GJB3 or GJB4 gene mutations alter the flow of molecules through gap junctions, which may also lead to premature cell death in the epidermis. The mechanisms by which epidermal damage and cell death contribute to hyperkeratosis and erythematous areas are poorly understood.

Mutations in the GJA1 gene lead to the production of an abnormal connexin 43 protein that is unable to reach the cell surface to become part of gap junctions. Instead, after it is produced, the abnormal protein becomes trapped in a cell structure called the Golgi apparatus. It is unclear how a shortage of connexin 43 at the cell surface affects the structure of gap junctions in the epidermis, or how these changes result in the skin abnormalities characteristic of EKVP.

In some cases, people with EKVP do not have a known mutation in one of the three connexin genes described above. Mutations in at least one non-connexin gene have been reported in a very small number of affected people. Studies suggest that changes in other genes that have not been identified may also cause EKVP.

Normal Function

The GJA1 gene provides instructions for making a protein called connexin 43, which is one of 21 connexin proteins. Connexins play a role in cell-to-cell communication by forming channels, or gap junctions, between cells. Gap junctions allow for the transport of nutrients, charged particles (ions), and other small molecules that carry necessary communication signals between cells. In addition, connexin 43 attaches (binds) several signaling molecules that can relay communication signals inside the cell. Connexin 43 is found in many tissues such as the eyes, skin, bone, ears, heart, and brain, and it plays a role in their normal development and function.

Health Conditions Related to Genetic Changes

Craniometaphyseal dysplasia

A mutation in the GJA1 gene has been found to cause autosomal recessive craniometaphyseal dysplasia in a small number of people. This condition is characterized by thickening of bones in the skull (cranium) and widening of a region at the end of long bones known as the metaphysis. The mutation is present in both copies of the GJA1 gene. It changes a single protein building block (amino acid) in the connexin 43 protein: at position 239, the amino acid arginine is replaced with the amino acid glutamine (written as Arg239Gln or R239Q). It is unknown how this change affects the function of the connexin 43 protein or leads to the bone abnormalities characteristic of craniometaphyseal dysplasia.

Erythrokeratodermia variabilis et progressiva

At least two mutations in the GJA1 gene have been found to cause erythrokeratodermia variabilis et progressiva (EKVP), a skin disorder characterized by areas of hyperkeratosis, which is abnormally thickened skin, and temporarily reddened patches called erythematous areas. The GJA1 gene mutations that cause this disorder are present in one of the two copies of the gene in each cell. Each of the known mutations changes a single amino acid in the connexin 43 protein. These changes lead to the production of an abnormal version of the protein that is unable to reach the cell surface to become part of gap junctions. Instead, after it is produced, the abnormal protein becomes trapped in a cell structure called the Golgi apparatus. It is unclear how a shortage of connexin 43 at the cell surface affects the structure of gap junctions in the outermost layer of skin (epidermis), or how these changes result in the skin abnormalities characteristic of EKVP.

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Oculodentodigital dysplasia

At least 76 mutations in the GJA1 gene have been found to cause oculodentodigital dysplasia, a condition characterized by abnormalities of the eyes (oculo-), teeth (dento-), and fingers (digital). The GJA1 gene mutations that cause this disorder are usually present in one of the two copies of the gene in each cell. Most of these mutations change an amino acid in connexin 43. A different type of change in the GJA1 gene causes people to have oculodentodigital dysplasia with palmoplantar keratoderma. Palmoplantar keratoderma is a condition that causes skin on the palms of the hands and the soles of the feet to become thick, scaly, and calloused. The mutation that causes this condition deletes two DNA building blocks (nucleotides) to create a premature stop signal in the instructions for making connexin 43. As a result, an abnormally short, nonfunctional protein is produced.

Gap junctions formed with abnormal connexin 43 proteins are often permanently closed, preventing the transport of any molecules. Some mutations prevent connexin 43 proteins from traveling to the cell surface where they are needed to form gap junctions. These disruptions impair communication between cells, which is thought to cause the eye, tooth, and finger abnormalities characteristic of oculodentodigital dysplasia.

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Heterotaxy syndrome

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Other disorders

Mutations in one copy of the GJA1 gene in each cell can cause isolated syndactyly type III, which is characterized by fusion of the ring and pinky fingers (fourth and fifth fingers) and sometimes shortening of the pinky finger. Syndactyly type III is a characteristic feature in oculodentodigital dysplasia (described above); however, some people have syndactyly type III without other features of oculodentodigital dysplasia, which is known as isolated syndactyly type III. It is unclear why some people with GJA1 gene mutations develop only the finger abnormalities and others have additional developmental abnormalities characteristic of oculodentodigital dysplasia.

A mutation in one copy of the GJA1 gene has been found to cause palmoplantar keratoderma and congenital alopecia 1, a condition characterized by skin problems, an absence of hair from birth (congenital alopecia), and often nail abnormalities. The mutation identified in this disorder leads to production of an altered connexin 43 protein. Channels made with the altered protein open more easily than normal, increasing the transport of molecules. Researchers suggest that abnormal signaling in cells that form the skin, hair, and nails results in the features characteristic of palmoplantar keratoderma and congenital alopecia 1.

Other mutations in one copy of the GJA1 gene in each cell have been found in a small number of people who have died suddenly with no known cause in infancy (sudden infant death syndrome) or early adulthood (sudden unexplained nocturnal death). Doctors suspect that abnormalities of heart function associated with GJA1 gene mutations may contribute to sudden death. It is thought that other genetic and environmental factors, many of which have not been identified, also play a part in determining the risk of these disorders. Mutations in one copy of the GJA1 gene may also contribute to heart malformations, although the role of such a genetic change is unclear.

Other Names for This Gene

• connexin 43
• connexin43
• CX43
• Cx43α1
• CXA1_HUMAN
• gap junction 43 kDa heart protein
• gap junction protein, alpha 1, 43kDa
• gap junction protein, alpha-like

Genomic Location

Normal Function

The GJB3 gene provides instructions for making a protein called gap junction beta 3, more commonly known as connexin 31. This protein is part of the connexin family, a group of proteins that form channels called gap junctions on the surface of cells. Gap junctions open and close to regulate the flow of nutrients, charged atoms (ions), and other signaling molecules from one cell to another. They are essential for direct communication between neighboring cells.

Connexin 31 is found in several different parts of the body, including the outermost layer of the skin (the epidermis) and structures of the inner ear. Connexin 31 plays a role in the growth and maturation of cells in the epidermis. The exact role of this protein in the inner ear is less clear, although it appears to be involved in hearing.

Health Conditions Related to Genetic Changes

Erythrokeratodermia variabilis et progressiva

At least 15 GJB3 gene mutations have been identified in people with erythrokeratodermia variabilis et progressiva (EKVP), a skin disorder characterized by areas of hyperkeratosis, which is abnormally thickened skin, and temporarily reddened patches called erythematous areas. Each of these mutations changes a single protein building block (amino acid) in connexin 31. Studies suggest that the abnormal protein produced from certain GJB3 gene mutations can build up in a cell structure called the endoplasmic reticulum (ER), triggering a harmful process known as ER stress. Researchers suspect that ER stress damages cells in the epidermis and leads to their premature death. Other GJB3 gene mutations result in the production of abnormal proteins that may form channels that do not function properly, which may also lead to premature cell death in the epidermis. In addition, abnormal connexin 31 proteins may interact with other connexin proteins, preventing the formation or function of other types of gap junctions. The mechanisms by which epidermal damage and cell death contribute to hyperkeratosis and erythematous areas are poorly understood.

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Other Names for This Gene

• connexin 31
• CX31
• CXB3_HUMAN
• DFNA2
• gap junction protein, beta 3, 31kDa
• PNHI

Genomic Location

Normal Function

The GJB4 gene provides instructions for making a protein called gap junction beta 4, more commonly known as connexin 30.3. This protein is part of the connexin family, a group of proteins that form channels called gap junctions on the surface of cells. Gap junctions open and close to regulate the flow of nutrients, charged atoms (ions), and other signaling molecules from one cell to another. They are essential for direct communication between neighboring cells.

Connexin 30.3 is found in several different tissues, including the outermost layer of the skin (the epidermis). This protein appears to play a role in the growth and maturation of epidermal cells.

Health Conditions Related to Genetic Changes

Erythrokeratodermia variabilis et progressiva

At least eight GJB4 gene mutations have been identified in people with erythrokeratodermia variabilis et progressiva (EKVP), a skin disorder characterized by areas of hyperkeratosis, which is abnormally thickened skin, and temporarily reddened patches called erythematous areas. Each of these mutations changes a single protein building block (amino acid) in connexin 30.3. Studies suggest that the abnormal protein can build up in a cell structure called the endoplasmic reticulum (ER), triggering a harmful process known as ER stress. Researchers suspect that ER stress damages cells in the epidermis and leads to their premature death. The mechanisms by which epidermal damage and cell death contribute to hyperkeratosis at erythematous areas are poorly understood.

Other Names for This Gene

• connexin 30.3
• connexin-30.3
• CX30.3
• CXB4_HUMAN
• EKV
• gap junction beta-4 protein
• gap junction protein, beta 4, 30.3kDa

Genomic Location

EKVP is most often inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new gene mutations and occur in people with no history of the disorder in their family. Very rarely, the mutation is found in some of the body's cells but not others. In these individuals, the condition is described as mosaic EKVP or inflammatory linear verrucous epidermal nevus (ILVEN). In mosaic EKVP, the characteristic skin abnormalities affect a small region of the body and usually occur on just one side. They may follow a pattern on the skin known as the lines of Blaschko.

A few studies have shown that EKVP can also have an autosomal recessive pattern of inheritance. However, this inheritance pattern has been reported in only a small number of affected families. Autosomal recessive inheritance means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

EKVP is a rare disorder; its prevalence is unknown. More than 200 cases have been reported in the medical literature.