ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis

J Invest Dermatol. 2018 Feb;138(2):291-300. doi: 10.1016/j.jid.2017.08.045.

Marwa Chourabi ¹, Mei Shan Liew ², Shawn Lim ², Dorra H'mida-Ben Brahim ³, Lobna Boussofara ⁴, Liang Dai ², Pui Mun Wong ⁵, Jia Nee Foo ⁶, Badreddine Sriha ⁷, Kim Samirah Robinson ⁸, Simon Denil ⁸, John Ea Common ⁹, Ons Mamaï ¹⁰, Youcef Ben Khalifa ¹¹, Mathieu Bollen ¹², Jianjun Liu ⁶, Mohamed Denguezli ⁴, Carine Bonnard ⁵, Ali Saad ³, Bruno Reversade ¹³

Affiliations

1 Laboratory of Human Genetics and Embryology, Institute of Medical Biology, A*STAR, Singapore, Singapore; Laboratory of Human Cytogenetic, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse, Tunisia.
2 L'Oréal Research & Innovation, Singapore, Singapore.
3 Laboratory of Human Cytogenetic, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse, Tunisia.
4 Department of Dermatology and Venerology, Farhat Hached University Hospital, Sousse, Tunisia.
5 Laboratory of Human Genetics and Embryology, Institute of Medical Biology, A*STAR, Singapore, Singapore.
6 Genome Institute of Singapore, A*STAR, Singapore, Singapore.
7 Department of Pathological Anatomy and Cytology, Farhat Hached University Hospital, Sousse, Tunisia.
8 Laboratory of Epithelial Biology, Institute of Medical Biology, A*STAR, Singapore, Singapore.
9 Laboratory of Skin Barrier, Institute of Medical Biology, A*STAR, Singapore, Singapore.
10 Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California, USA.
11 L'Oréal Research & Innovation, Paris, France.
12 Laboratory of Biosignaling and Therapeutics, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
13 Laboratory of Human Genetics and Embryology, Institute of Medical Biology, A*STAR, Singapore, Singapore. Electronic address: bruno@reversade.com.

PMID: 28964717 DOI: 10.1016/j.jid.2017.08.045

Abstract

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 whole-exome Sequencing, a biallelic p.Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (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.

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