CARD14 – Pityriasis Rubra Pilaris

Autosomal‐dominant mutations in CARD14, encoding a keratinocyte‐expressed scaffold protein for NF-κB activation, underlie familial and sporadic forms of pityriasis rubra pilaris (PRP). Initial linkage in four unrelated pedigrees mapped PRP to 17q25.3 (overlapping PSORS2) and exome sequencing identified three heterozygous CARD14 mutations co-segregating with disease (PMID:22703878).

Genetic evidence includes at least 10 affected individuals across these families and additional case series showing autosomal-dominant inheritance with complete or incomplete penetrance. Segregation of missense variants in the CARD–coiled-coil domain confirms allelism with psoriasis susceptibility (PMID:22703878; PMID:27760266).

Case reports broaden the variant spectrum: c.412G>A (p.Glu138Lys) in a sporadic type V patient, c.356T>G (p.Met119Arg) in a mother–son dyad, and other substitutions (e.g., p.Gln136Leu) highlight recurrent charge‐altering events in PRP (PMID:26130407; PMID:28301045).

CARD14 variants are predominantly missense and cluster in the N-terminal coiled-coil region; no truncating alleles have been reported. Recurrent Glu138 substitutions and Met119 alterations suggest mutational hotspots rather than private alleles.

Functional assays demonstrate gain-of-function: patient keratinocytes show increased NF-κB p65 nuclear translocation and reporter activity, and murine models of CARD14E138A recapitulate epidermal hyperplasia and inflammatory cytokine expression (PMID:30018619; PMID:22703878).

Clinically, PRP patients with CARD14 mutations respond to biologics targeting IL-12/23 (ustekinumab), underscoring the therapeutic potential of NF-κB pathway modulation in this cohort (PMID:28301045).

While rare CARD14 polymorphisms also occur in sporadic PRP and psoriasis, the convergence of segregation, functional concordance, and therapeutic response supports a strong gene-disease relationship. Genetic testing for CARD14 mutations aids diagnosis and guides targeted intervention.

Key Take-home: Autosomal-dominant CARD14 gain-of-function variants cause PRP via enhanced NF-κB signaling; identification informs diagnosis and targeted biologic therapy.

References

• American journal of human genetics • 2012 • Familial pityriasis rubra pilaris is caused by mutations in CARD14. PMID:22703878
• JAMA dermatology • 2017 • Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations. PMID:27760266
• Frontiers in immunology • 2018 • Nuclear Factor κB Activation in a Type V Pityriasis Rubra Pilaris Patient Harboring MultipleCARD14 Variants. PMID:30018619
• Journal of dermatology • 2016 • CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis. PMID:26130407
• The British journal of dermatology • 2018 • Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14. PMID:28301045

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