Cole Disease Results from Mutations in ENPP1
Ori Eytan1, Fanny Morice-Picard, Ofer Sarig
1Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 642395, Israel; Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
American Journal of Human Genetics
|October 1, 2013
Summary
Researchers identified genetic mutations in ENPP1 as the cause of Cole disease, a rare skin disorder. This discovery links abnormal keratinization, pigmentation, and calcification, revealing new insights into ENPP1-associated genetic conditions.
Area of Science:
- Genetics
- Dermatology
- Biochemistry
Background:
- Abnormal keratinization and pigmentation often coexist in skin disorders, suggesting a shared mechanism.
- Cole disease is a rare autosomal-dominant genodermatosis characterized by punctate keratoderma, hypopigmentation, and cutaneous calcifications.
Purpose of the Study:
- To decipher the genetic basis of Cole disease.
- To investigate the role of ENPP1 mutations in this genodermatosis.
Main Methods:
- Exome and direct sequencing were employed to identify causative genetic variants.
- Analysis focused on cosegregation of the disease phenotype with identified mutations in affected families.
Main Results:
- Three heterozygous ENPP1 mutations were found to cosegregate with the Cole disease phenotype in three unrelated families.
- All identified mutations affected cysteine residues within the somatomedin-B-like 2 (SMB2) domain of the ENPP1 protein.
- The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) enzyme generates inorganic pyrophosphate, a mineralization inhibitor.
Conclusions:
- Heterozygous ENPP1 mutations cause Cole disease, a distinct autosomal-dominant genodermatosis.
- This finding expands the known phenotypic spectrum of ENPP1-associated disorders, previously linked primarily to recessive calcification conditions.
- The study highlights a mechanistic link between keratinization, pigmentation, and mineralization processes in the skin.
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