Cole disease results from mutations in ENPP1

Ori Eytan, Fanny Morice-Picard, Ofer Sarig, Khaled Ezzedine, Ofer Isakov, Qiaoli Li, Akemi Ishida-Yamamoto, Noam Shomron, Tomer Goldsmith, Dana Fuchs-Telem, Noam Adir, Jouni Uitto, Seth J. Orlow, Alain Taieb*, Eli Sprecher

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The coexistence of abnormal keratinization and aberrant pigmentation in a number of cornification disorders has long suggested a mechanistic link between these two processes. Here, we deciphered the genetic basis of Cole disease, a rare autosomal-dominant genodermatosis featuring punctate keratoderma, patchy hypopigmentation, and uncommonly, cutaneous calcifications. Using a combination of exome and direct sequencing, we showed complete cosegregation of the disease phenotype with three heterozygous ENPP1 mutations in three unrelated families. All mutations were found to affect cysteine residues in the somatomedin-B-like 2 (SMB2) domain in the encoded protein, which has been implicated in insulin signaling. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which is responsible for the generation of inorganic pyrophosphate, a natural inhibitor of mineralization. Previously, biallelic mutations in ENPP1 were shown to underlie a number of recessive conditions characterized by ectopic calcification, thus providing evidence of profound phenotypic heterogeneity in ENPP1-associated genetic diseases.

Original languageEnglish
Pages (from-to)752-757
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 3 Oct 2013


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