protein O-fucosyltransferase 1
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.
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.