Cole Disease Results from Mutations in ENPP1.
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.
Department 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.
Ori
O
Eytan
Fanny
F
Morice-Picard
Ofer
O
Sarig
Khaled
K
Ezzedine
Ofer
O
Isakov
Qiaoli
Q
Li
Akemi
A
Ishida-Yamamoto
Noam
N
Shomron
Tomer
T
Goldsmith
Dana
D
Fuchs-Telem
Noam
N
Adir
Jouni
J
Uitto
Seth J
SJ
Orlow
Alain
A
Taieb
Eli
E
Sprecher
D002113:Calcification, Physiologic / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D017496:Hypopigmentation / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007642:Keratosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D017499:Porokeratosis / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D012871:Skin Diseases / Q000235:genetics*; D012873:Skin Diseases, Genetic / Q000235:genetics; D013002:Somatomedins / Q000235:genetics
D013002:Somatomedins; C016756:somatomedin B; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases