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: [email protected].
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.