Familial pityriasis rubra pilaris is caused by mutations in CARD14.
Pityriasis rubra pilaris (PRP) is a papulosquamous disorder phenotypically related to psoriasis. The disease has been occasionally shown to be inherited in an autosomal-dominant fashion. To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP. We initially mapped PRP to 17q25.3, a region overlapping with psoriasis susceptibility locus 2 (PSORS2 [MIM 602723]). Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14. CARD14 was found to be specifically expressed in the skin. CARD14 is a known activator of nuclear factor kappa B signaling, which has been implicated in inflammatory disorders. Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals. The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14.
Department of Dermatology, Tel Aviv Sourasky Medical Center, Israel.
Dana
D
Fuchs-Telem
Ofer
O
Sarig
Maurice A M
MA
van Steensel
Ofer
O
Isakov
Shirli
S
Israeli
Janna
J
Nousbeck
Katharina
K
Richard
Veronique
V
Winnepenninckx
Marigje
M
Vernooij
Noam
N
Shomron
Jouni
J
Uitto
Philip
P
Fleckman
Gabriele
G
Richard
Eli
E
Sprecher
D000328:Adult; D001483:Base Sequence; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010916:Pityriasis Rubra Pilaris / Q000235:genetics*; D012867:Skin / Q000378:metabolism
D053468:CARD Signaling Adaptor Proteins; D008565:Membrane Proteins; C426243:CARD14 protein, human; D006162:Guanylate Cyclase