A genetic mutation that affects the production of the skin pigment melanin is associated with a previously unknown form of Cole disease—a rare condition characterized by unusually light-colored and dark-colored skin areas as well as spots of thickened skin on the palms of the hands and the soles of the feet.

A team led by Bruno Reversade at the A*STAR Institute of Medical Biology analyzed the DNA of eight patients from three unrelated families in Sousse, Tunisia, presenting with the clinical features of Cole disease. All patients developed the symptoms within the first 3 months of life and went on to develop eczema.

Until now, Cole disease has been reported to follow a dominant pattern of inheritance, which means one copy of an altered gene in each cell is enough to cause pigmentation abnormalities. However, parents and siblings of these eight patients carrying one copy of an altered gene were unaffected, indicating that their form of the disease requires two copies of the altered gene and thus, follows a recessive pattern of inheritance.

The team found that the eight patients had a common mutation in the gene encoding ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), a protein that regulates the production of extracellular inorganic pyrophosphate (PPi). PPi prevents the accumulation of calcium in the body and has a key role in bone development and the formation of abnormal calcium deposits in soft tissues, including skin.

Interestingly, the identified mutation differs from others in the same gene that have been associated with the dominant form of Cole disease. Previous studies have shown that mutations affecting the SMB2 domain of ENPP1 protein disrupt the transport of melanin from the cells in which it is produced (melanocytes) to epidermal cells in response to insulin.

With the help of L’Oréal Research, Reversade and colleagues identified a mutation in a different region of the ENPP1 protein. As Reversade explains: “We found a mutation that affects the SMB1 domain of ENPP1 and interferes with the protein’s ability to pair with itself.”

Further examination of the skin from a patient and their unaffected sibling revealed that in the patient’s skin there was an upregulation of melanin production in the darker skin regions and a downregulation in the lighter-colored areas compared with normal skin, indicating that the SMB1 mutation impairs melanin production.

“The association of different ENPP1 mutations with Cole disease suggests that there is a spectrum of skin pigmentation anomalies that share some clinical features, but have different patterns of inheritance and severity,” Reversade concludes.