What are the key features of Cole disease, and how is it diagnosed?

ENPP1 gene

The ENPP1 gene provides instructions for making a protein that regulates mineral deposits in the body and plays a role in insulin signaling.

Normal Function

The ENPP1 gene provides instructions for making a protein that helps break down a molecule called adenosine triphosphate (ATP). Specifically, the ENPP1 protein breaks down ATP that is found outside of cells (extracellular). Extracellular ATP is quickly broken down into other molecules called adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate is important for preventing the accumulation of abnormal deposits of calcium (calcification) and other minerals (mineralization) in the body.

The ENPP1 protein also plays a role in the cell signaling that occurs in response to the hormone insulin. Part of the ENPP1 protein, called the SMB2 domain, interacts with the insulin receptor, which is a protein that binds to insulin and initiates cell signaling. Insulin helps regulate levels of blood glucose by controlling how much glucose passes from the bloodstream into cells to be used as energy. Insulin is also important for the maintenance of the outer layer of skin (the epidermis) and helps control the transport of the pigment melanin from melanocytes to keratinocytes, as well as the development of keratinocytes.

Health Conditions Related to Genetic Changes

Cole disease

Variants in the ENPP1 gene have been identified in people with Cole disease, which is characterized by areas of unusually light-colored skin (hypopigmentation) and spots of thickened skin on the palms and soles (punctate palmoplantar keratoderma). These variants alter the SMB2 domain, impairing the protein's function in melanin transport and keratinocyte development. While the protein's role in calcification may also be impaired, these variants do not seem to affect blood glucose control.

Generalized arterial calcification of infancy

Variants in the ENPP1 gene have been identified in individuals with generalized arterial calcification of infancy (GACI), a life-threatening disorder characterized by calcification in the arteries. These variants produce an altered protein that cannot properly assist in the breakdown of ATP and the production of pyrophosphate. The resulting reduced availability of pyrophosphate interferes with the regulation of calcification in the body.

Other disorders

Hypophosphatemic rickets: Variants in the ENPP1 gene are a rare cause of this condition, which is characterized by low levels of phosphate in the blood (hypophosphatemia) and skeletal abnormalities. These variants increase the amount of a protein called fibroblast growth factor 23, which reduces the phosphate available for bone development.
Type 2 diabetes: A normal variation (polymorphism) in the ENPP1 gene, where the amino acid glutamine replaces lysine at position 121 (the Q121 variant), has been associated with an increased risk of type 2 diabetes. This variant inhibits the function of the insulin receptor more than the standard version, increasing insulin resistance.