Dowling-Degos disease is a skin condition characterized by a lacy or net-like (reticulate) pattern of abnormally dark skin coloring (hyperpigmentation), particularly in the body's folds and creases. These skin changes typically first appear in the armpits and groin area and can later spread to other skin folds such as the crook of the elbow, back of the knee, and under the breasts. Less commonly, pigmentation changes can also occur on the neck, wrists, back of the hands, face, scalp, scrotum, and vulva. These areas of hyperpigmentation typically cause no health problems.

Individuals with Dowling-Degos disease may also have dark spots (lesions) on the face and back that resemble blackheads, red bumps around the mouth that resemble acne, or pitted scars on the face similar to acne scars but with no history of acne. Fluid-filled sacs within the hair follicle (pilar cysts) may develop, most commonly on the scalp. Rarely, affected individuals have patches of skin that are unusually light in color (hypopigmented).

In rare cases, individuals with Dowling-Degos disease experience itching (pruritus) or burning sensations on the skin. These feelings can be triggered by UV light, sweating, or friction on the skin.

The pigmentation changes characteristic of Dowling-Degos disease typically begin in late childhood or in adolescence, although in some individuals, features of the condition do not appear until adulthood. New areas of hyperpigmentation tend to develop over time, and the other skin lesions tend to increase in number as well. While the skin changes associated with Dowling-Degos disease may cause distress or anxiety, they typically cause no other health problems.

A condition called Galli-Galli disease has signs and symptoms similar to those of Dowling-Degos disease. In addition to pigmentation changes, individuals with Galli-Galli disease also have a breakdown of cells in the outer layer of skin (acantholysis). Acantholysis can cause skin irritation and itchiness and lead to reddened or missing patches of skin (erosions). These conditions used to be considered two separate disorders, but Galli-Galli disease and Dowling-Degos disease are now regarded as the same condition.

Mutations in the KRT5, POFUT1, or POGLUT1 gene cause most cases of Dowling-Degos disease.

The KRT5 gene provides instructions for making a protein called keratin 5, which is produced in cells called keratinocytes in the outer layer of the skin (the epidermis). Keratin 5 is one component of molecules called keratin intermediate filaments. These filaments assemble into strong networks that help attach (bind) keratinocytes together and anchor the epidermis to underlying layers of skin. Researchers believe that keratin 5 may also play a role in transporting melanosomes, which are pigment-carrying structures found in skin cells called melanocytes. The transport of these structures from melanocytes into keratinocytes is important for the development of normal skin coloration (pigmentation).

The POFUT1 and POGLUT1 genes provide instructions for making proteins that add different sugar molecules to proteins called Notch receptors. Notch receptors are a family of proteins that are involved in a signaling pathway that guides normal development of many tissues throughout the body, both before birth and throughout life. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. The addition of sugar molecules to Notch receptors changes the shape of the receptors, allowing them to bind to their ligands and trigger signaling in the pathway. In skin cells, Notch signaling likely plays a role in maintaining precursor cells that mature into melanocytes and regulating interactions between melanocytes and keratinocytes.

KRT5 gene mutations that cause Dowling-Degos disease lead to a decrease in functional keratin 5 protein. A loss of keratin 5 can impair the formation of keratin intermediate filaments. As a result, the normal organization of the epidermis is altered, leading to the development of different types of skin lesions. Additionally, a decrease in keratin 5 may disrupt the transfer of pigment-carrying melanosomes from melanocytes to keratinocytes, where they are needed for the development of normal skin pigmentation. This disruption of melanosome transport is thought to cause the pigmentation abnormalities seen in individuals with Dowling-Degos disease.

Mutations in the POFUT1 or POGLUT1 gene result in a protein with little or no function. As a result, the protein is less able or unable to add sugar molecules to Notch receptors. Without these sugar molecules, Notch receptors cannot bind to their ligands and the Notch signaling pathway is halted. Because the varied functions of the Notch signaling pathway affect many body systems and Dowling-Degos disease affects only the skin, it is unclear whether the signs and symptoms of this condition are due to impaired Notch signaling or disruption of an unknown function of the protein in melanocytes or other skin cells.

Mutations in other genes, some of which have not been identified, are responsible for the remaining cases of Dowling-Degos disease.

Normal Function

The KRT5 gene provides instructions for making a protein called keratin 5. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, and nails. Keratin 5 is produced in cells called keratinocytes in the outer layer of the skin (the epidermis).

Keratin 5 partners with a similar protein, keratin 14 (produced from the KRT14 gene), to form molecules called keratin intermediate filaments. These filaments assemble into strong networks that help attach keratinocytes together and anchor the epidermis to underlying layers of skin. The network of keratin intermediate filaments provides strength and resiliency to the skin and protects it from being damaged by friction and other everyday physical stresses.

Researchers believe that keratin 5 interacts with pigment-producing cells called melanocytes to transport melanosomes, which are cellular structures within melanocytes that carry pigment called melanin. The transport of these structures from melanocytes to keratinocytes is important for the development of normal skin coloration (pigmentation).

Health Conditions Related to Genetic Changes

Dowling-Degos disease

At least five mutations in the KRT5 gene have been found to cause Dowling-Degos disease. This condition results in various skin abnormalities, including a characteristic lacy pattern of abnormally dark skin coloring (hyperpigmentation) that occurs mostly in the body's folds and creases. Most KRT5 gene mutations that cause Dowling-Degos disease lead to the production of a keratin 5 protein that is abnormally small and nonfunctional or prevent any protein from being produced from the gene. A shortage (deficiency) of functional keratin 5 impairs the formation of keratin intermediate filaments. As a result, the organization of the epidermis is altered, leading to the development of different types of skin abnormalities. Additionally, a deficiency of keratin 5 may disrupt the movement of pigment-carrying melanosomes into keratinocytes, where they are needed for the development of normal skin pigmentation. This disruption of melanosome transport is thought to cause the pigmentation abnormalities seen in individuals with Dowling-Degos disease.

Epidermolysis bullosa simplex

More than 130 mutations in the KRT5 gene have been identified in people with epidermolysis bullosa simplex, a condition that causes the skin to be very fragile and to blister easily. Most of these mutations alter single protein building blocks (amino acids) used to make keratin 5. The most severe form of epidermolysis bullosa simplex, the Dowling-Meara type, usually results from changes in regions of keratin 5 that are essential for the normal assembly of keratin intermediate filaments. Milder forms of the disorder, including the localized type (formerly called the Weber-Cockayne type) and a form known as the other generalized type (formerly called the Koebner type), are often caused by changes affecting less critical regions of the protein. Another form of the disorder called epidermolysis bullosa simplex with mottled pigmentation typically results from a particular KRT5 mutation. This mutation replaces the amino acid proline with the amino acid leucine at protein position 25 (written as Pro25Leu or P25L).

The KRT5 gene mutations responsible for epidermolysis bullosa simplex change the structure and function of keratin 5, preventing it from partnering effectively with keratin 14 and interfering with the assembly of the keratin intermediate filament network. Mutations that cause severe forms of the disorder badly disrupt the assembly of keratin intermediate filaments, while mutations that result in milder forms impair keratin filament assembly to a lesser degree. A disruption in this network makes keratinocytes fragile and prone to rupture. Minor trauma to the skin, such as rubbing or scratching, can cause these cells to break down, resulting in the formation of painful, fluid-filled blisters.

Other Names for This Gene

• 58 kda cytokeratin
• CK5
• cytokeratin 5
• EBS2
• K2C5_HUMAN
• K5
• keratin 5, type II
• keratin, type II cytoskeletal 5
• Keratin-5
• KRT5A

Genomic Location

Normal Function

The POFUT1 gene provides instructions for making a protein called protein O-fucosyltransferase 1. This protein is located in a cell structure called the endoplasmic reticulum, which helps with protein processing and transport. Protein O-fucosyltransferase 1 adds sugar molecules, specifically a sugar called fucose, to other proteins called Notch receptors. Notch receptors are a family of proteins that are involved in a signaling pathway that guides normal development of many tissues throughout the body, both before birth and throughout life. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Attachment of a ligand into a Notch receptor triggers signaling in the pathway.

The addition of fucose molecules alters the shape of the Notch receptor. The receptor is then able to attach (bind) to its ligand and trigger signaling. Through its integral role in Notch receptor function, protein O-fucosyltransferase 1 allows the Notch pathway to proceed. The Notch pathway regulates a variety of processes including the specialization of cells into certain cell types that perform particular functions in the body (cell fate determination). It also plays a role in cell growth and division (proliferation), maturation (differentiation), and self-destruction (apoptosis).

In skin cells, Notch signaling likely plays a role in the maintenance of precursor cells that mature into pigment-producing skin cells called melanocytes and may regulate interactions between melanocytes and other skin cells called keratinocytes.

Health Conditions Related to Genetic Changes

Dowling-Degos disease

At least 13 mutations in the POFUT1 gene have been found to cause Dowling-Degos disease. This condition results in various skin abnormalities, including a characteristic lacy pattern of abnormally dark skin coloring (hyperpigmentation) that occurs most often in the body's folds and creases.

The POFUT1 gene mutations that cause Dowling-Degos disease either lead to an abnormally short protein with no function or change single protein building blocks (amino acids), resulting in a partial loss of protein function. As a result, protein O-fucosyltransferase 1 is less able or unable to add fucose molecules to Notch receptors. Without these sugar molecules, Notch receptors cannot bind to their ligands and the Notch pathway is halted. Because the varied functions of the Notch pathway affect many body systems and Dowling-Degos disease affects only the skin, it is unclear whether the signs and symptoms of this condition are due to impaired Notch signaling or disruption of an unknown function of protein O-fucosyltransferase 1 in melanocytes or other skin cells.

Other Names for This Gene

• FUT12
• KIAA0180
• O-Fuc-T
• o-fucosyltransferase protein
• O-FucT-1
• O-FUT
• OFUCT1
• peptide-O-fucosyltransferase 1

Genomic Location

Normal Function

The POGLUT1 gene provides instructions for making a protein called protein O-glucosyltransferase 1. This protein is located in a cell structure called the endoplasmic reticulum, which helps with protein processing and transport. Protein O-glucosyltransferase 1 adds sugar molecules, specifically a sugar called glucose, to other proteins called Notch receptors. Notch receptors are a family of proteins that are involved in a signaling pathway that guides normal development of many tissues throughout the body, both before birth and throughout life. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Attachment of a ligand into a Notch receptor triggers signaling in the Notch pathway.

The addition of glucose molecules alters the shape of the Notch receptor. The receptor is then able to attach (bind) to its ligand and trigger signaling. Through its integral role in Notch receptor function, protein O-glucosyltransferase 1 allows the Notch pathway to proceed. The Notch pathway regulates a variety of processes including the specialization of cells into certain cell types that perform particular functions in the body (cell fate determination). It also plays a role in cell growth and division (proliferation), maturation (differentiation), and self-destruction (apoptosis).

In skin cells, Notch signaling likely plays a role in the maintenance of precursor cells that mature into pigment-producing skin cells called melanocytes and may regulate interactions between melanocytes and other skin cells called keratinocytes. Protein O-glucosyltransferase 1 is found in high levels in skin cells, particularly in the outermost layer of skin (epidermis) where melanocytes are abundant, and may have additional functions in the skin besides its involvement in Notch signaling.

Health Conditions Related to Genetic Changes

Dowling-Degos disease

At least 11 mutations in the POGLUT1 gene have been found to cause Dowling-Degos disease. This condition results in various skin abnormalities, including a characteristic lacy pattern of abnormally dark skin coloring (hyperpigmentation) that occurs most often in the body's folds and creases.

Most of the POGLUT1 gene mutations that cause Dowling-Degos disease lead to an abnormally short protein with no function or change single protein building blocks (amino acids) resulting in a partial loss of protein function. As a result, protein O-glucosyltransferase 1 is less able or unable to add glucose molecules to Notch receptors. Without these sugar molecules, Notch receptors cannot bind to their ligands and the Notch pathway is halted. Because the varied functions of the Notch pathway affect many body systems and Dowling-Degos disease affects only the skin, it is unclear whether the signs and symptoms of this condition are due to impaired Notch signaling or disruption of an unknown function of protein O-glucosyltransferase 1 in melanocytes or other skin cells.

Limb-girdle muscular dystrophy

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Other Names for This Gene

• C3orf9
• CAP10-like 46 kDa protein
• CLP46
• hCLP46
• hRumi
• KDELC family like 1
• KDELCL1
• KTEL (Lys-Tyr-Glu-Leu) containing 1
• KTEL motif-containing protein 1
• KTELC1
• LGMD2Z
• MDS010
• MGC32995
• O-glucosyltransferase Rumi homolog
• protein O-xylosyltransferase
• Rumi

Genomic Location

• Dark skin coloring (hyperpigmentation) in body folds and creases
• Skin nodules (abnormal growths)
• Skin abscesses (pus-filled bumps)
• Pitted scars

Dowling-Degos disease appears to be a rare condition, although its prevalence is unknown.