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ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis
Marwa Chourabi1, Mei Shan Liew2, Shawn Lim2
1Laboratory 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.
The Journal of Investigative Dermatology
|October 2, 2017
Summary
A novel recessive mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) causes a severe form of Cole disease. This genetic defect in melanocytes leads to widespread skin pigmentation abnormalities, including dyschromatosis universalis hereditaria.
Area of Science:
- Genetics
- Dermatology
- Molecular Biology
Background:
- Cole disease is a dominant genodermatosis affecting skin pigmentation.
- Previous research has focused on dominant inheritance patterns for this condition.
Purpose of the Study:
- To investigate the genetic basis of a pigmentary genodermatosis with overlapping features of Cole disease and dyschromatosis universalis hereditaria, inherited in a recessive manner.
- To identify the specific gene and mutation responsible for this recessive form of the disease.
Main Methods:
- Homozygosity mapping and whole-exome sequencing were employed to identify genetic variants in affected individuals.
- Histological and RNA-sequencing analyses were performed on patient skin and melanocytes.
- Functional studies assessed the impact of the identified mutation on ENPP1 enzyme activity.
Main Results:
- A biallelic p.Cys120Arg mutation in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene was identified in all patients.
- This mutation impairs ENPP1 homodimerization, affecting melanocyte development and pigmentation pathways.
- Skin histology revealed defects originating from melanocytes, as keratinocytes do not express ENPP1.
Conclusions:
- Germline ENPP1 mutations, particularly cysteine-specific ones, cause a spectrum of dyschromatosis.
- The p.Cys120Arg ENPP1 allele represents a recessive and more severe variant of Cole disease.
- The findings highlight the critical role of ENPP1 in melanocyte function and skin pigmentation.
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