ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis

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 Mamaï, Youcef Ben Khalifa, Mathieu Bollen, Jianjun Liu, Mohamed Denguezli, Carine Bonnard, Ali Saad, Bruno Reversade

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.
Original languageEnglish (US)
Pages (from-to)291-300
Number of pages10
JournalJournal of Investigative Dermatology
Volume138
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

Fingerprint

Dive into the research topics of 'ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis'. Together they form a unique fingerprint.

Cite this