Details

Autor(en) / Beteiligte

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

Titel

ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis

Ist Teil von

• Journal of investigative dermatology, 2018-02, Vol.138 (2), p.291-300

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.