ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis

ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis

Journal of Investigative Dermatology

10.1016/j.jid.2017.08.045

http://dx.doi.org/10.1016/j.jid.2017.08.045

Marwa Chourabi, Mei Shan Liew, Shawn Lim, Dorra H’mida-Ben Brahim, Lobna Boussofara, Liang Dai, Pui Mun Wong, Jia Nee Foo, Badreddine Sriha, Kim Samirah Robinson, Simon Denil, John EA Common, Ons Mamai, Youcef Ben Khalifa, Mathieu Bollen, Jianjun Liu, Mohamed Denguezli, Carine Bonnard, Ali Saad, Bruno Reversade

Genetics and Molecular Biology

28 September 2017

Chourabi, M., Liew, M. S., Lim, S., H’mida-Ben Brahim, D., Boussofara, L., Dai, L., Wong, P. M., Foo, J. N., Sriha, B., Robinson, K. S., Denil, S., Common, J. E., Mamaï, O., Ben Khalifa, Y., Bollen, M., Liu, J., Denguezli, M., Bonnard, C., Saad, A., & Reversade, B. (2018). ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis. Journal of Investigative Dermatology, 138(2), 291–300. https://doi.org/10.1016/j.jid.2017.08.045

Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study, we investigated eight patients affected with an overlapping genodermatosis after recessive inheritance. The patients presented with hypo- and hyperpigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and wholeexome sequencing, a biallelic p.Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homodimerization of the ENPP1 enzyme that is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin that were likely to originate from defective melanocytes because keratinocytes do not express ENPP1. Consistently, RNA-sequencing analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease.

Attribution 4.0 International (CC BY 4.0)

This work was partly funded by the Skin Research Institute of Singapore (SRIS) and a Strategic Positioning Fund on Genetic Orphan Diseases from A*STAR, Singapore. This work was partly funded by L’Ore ́al Research & Innovation Department. MSL, SL, LD, and YBK are employees of L’Ore ́al.

This work was partly funded by L’Ore ́al Research & Innovation Department.

https://oar.a-star.edu.sg/communities-collections/articles/20111

0022-202X

Skin Research Lab