Cole disease : Role of ENPP1 in regulation of pigmentation and epidermal differentiation

Cole disease is a rare autosomal dominant disorder characterized by hypopigmented macules and hyperkeratosis. However, patient may also have hyperpigmented macuIes. In hypopigmented macules, a normal number of pigmented melanocytes but decreased melanin content in keratinocytes, suggesting an impairment of melanosome transfer, has  been reported. Five mutations in somatomedin-B-like domains of EctoNucleotide Pyrophospahatase /Phosphodiesterase 1 (ENPP1) have been identified in five families with Cole disease. To study the role of ENPP1 in pigmentation and skin differentiation, we, first, reconstructed skin with cells from one patient with Cole disease and surprisingly Cole melanocytes were able to induced thickening of epidermal reconstructs. Since this disease is rare, we transduced melanocytes and keratinocytes with lentivectors coding wild-type (WT) ENPP1 or coding the first three mutations (M) identified in ENPP1. In melanocytes, at the protein level, expression of TRP-1 and tyrosinase but not of MITF seemed inversely correlated to the level of expression of mutated ENPP1. However, increased ENPP1 mRNA was not associated with decrease in MITF, tyrosinase, TRP-1 and TRP-2  mRNA. We could even observed an increase in these enzymes. Our results suggest that melanin synthesis modulation by ENPP1 is complex and may induced hyper or hypopigmentation. Reconstructions with melanocytes transduced with mutated ENPP1 were not thicker than those reconstructed with melanocytes transduced with WT melanocytes. But reconstructions with cells co-transduced with WT and mutated ENPP1 forms seemed thicker than those with WT alone. We also used pharmacological inhibitor of ENPP1 on monolayer cell culture. Secretome from melanocytes treated with ENPP1 inhibitors modulated expression of keratin 5 in keratinocytes whereas direct inhibition of ENPP1 in keratinocytes seemed less effective. Thus mutations of ENPP1 seemed directly implicated in establishing and sustaining hypo or hyperpigmentation in Cole Disease. Furthermore melanocytes seemed implicated in establishment of hyperkeratosis in Cole Disease.