Aberrant CARD14 function might cause defective barrier formation

Abstract

We read with great interest the recent report by Peled et al 1 on how loss-of-function mutations in CARD14 (caspase recruitment domain family, member 14) are associated with a severe variant of atopic dermatitis (AD). 1 CARD14 encodes a known regulator of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), and dominant gain-of-function mutations in CARD14 cause psoriasis and related disorders. 1,2 Peled et al 1 revealed that dominant negative mutations in CARD14 result in severe AD and decreased NF-kB signaling. 1 Their findings expand the spectrum of CARD14-associated phenotypes and shed light on the partially overlapping but also distinct pathophysiologic mechanisms underlying AD and psoriasis. We previously proposed that pityriasis rubra pilaris (PRP) type V, the atypical juvenile type, is a distinct variant of PRP that is caused by CARD14 mutations. 3 We had a unique case of PRP type V who showed eczematous lesions and high serum IgE and thymus and activation-regulated chemokine (TARC), which suggested defective barrier function. Our findings indicate that the pathogenesis of AD with CARD14 mutations might involve not only an imbalance of NF-kB/antimicrobial peptides but also defective skin barrier function.

A patient with CARD14‐associated papulosquamous eruptions showing atopic dermatitis‐like features

“…The present CARD14 variant, p.Asp176His, is known as a gain‐of‐function variant that causes increased NF‐κB activation 4 . We previously reported a case of PRP who showed cutaneous features of CAPE, eczematous lesions and moderately elevated serum IgE and TARC, which suggested defective barrier function 3 . In addition, Peled et al 5 .…”

“…Genomic DNA from the patient's peripheral blood leukocytes was used for Sanger sequencing analysis as described previously 1 . She had a previously reported heterozygous missense variant in CARD14 , c.526G>C (p.Asp176His) 1,3 . None of the 10 loss‐of‐function FLG mutations reported in the Japanese population was found in the genomic DNA of the patient.…”

The role of the CBM complex in allergic inflammation and disease

“…173 Eczematous lesions and both high IgE and thymusand activation-regulated chemokine were also found in 2 unrelated patients with the missense CARD14 mutation D176H in addition to their respective T H 17-associated diagnoses (pityriasis rubra pilaris and CARD14-associated papulosquamous eruption). 174,175 A sixth patient with the CARD14 missense Q223H had severe AD, multiple food allergies, and enteropathy in the context of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disease. 176 Although the underlying mechanisms are largely unknown, these studies illustrate the clinical heterogeneity of CARD14 mutations and expands the spectrum of CARD14-related inflammatory diseases to include T H 2related manifestations.…”

“…As discussed earlier, several CARD14 missense mutations (D176H, Q223H, I593T, and N737H) have been found in patients with AD or eczematous lesions. [173][174][175][176] Although the functional impacts of the D176H and Q223H mutations on CARD14 signaling are unclear, 5,179 the I593T and N737H mutations are DN mutations that attenuate keratinocyte NF-kB signaling. However, CARD14-deficient mice do not develop spontaneous AD, 165,180 suggesting that at least some low-level-but not absent-CARD14 signaling is required to promote AD.…”

KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease

“…Autoinflammatory keratinization disease (AiKD) is an umbrella term recently introduced to describe inflammatory keratinization diseases caused by mutations in single genes associated with autoinflammatory diseases (6,7). AiKDs are genetically heterogeneous, and their different subtypes show various clinical features, complications, and prognoses (8)(9)(10)(11). We propose that KLICK syndrome associated with the POMP mutation be categorized as an AiKD.…”