Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis

Peled, A.; Sarig, Ofer; Sun, Guangping; Samuelov, Liat; Chi, Aiping; Zhang, Yuan; DiMaggio, Tom; Nelson, Celeste; Stone, Kelly D.; Freeman, Alexandra F.; Malki, Liron; Vidal, Lucia Seminario; Chamarthy, Latha M.; Briskin, Valeria; Mohamad, Janan; Pavlovsky, Mor; Walter, Jolán E.; Milner, Joshua D.; Sprecher, Eli

doi:10.1016/j.jaci.2018.09.002

Cited by 63 publications

(53 citation statements)

References 65 publications

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“…27 Experimental knockout mouse models soon provided genetic evidence for the role of CBM proteins in activating major cell-signaling pathways, including NF-kB, c-Jun N-terminal kinase, and mTOR, [30][31][32][33][34][35][36][37][38] establishing the foundational knowledge that has empowered the recent identification of patients with mutations in each of these components (termed CBM-opathies). 1,[39][40][41][42][43][44][45][46][47][48][49] As a result, it is clear that CBM complexes have a prominent role in regulating human immunity and immunopathology.…”

Section: Discovery Of the Cbm Complexes And Germline Cbm-opathiesmentioning

confidence: 99%

Germline CBM-opathies: From immunodeficiency to atopy

Lu¹,

Biggs

Blanchard-Rohner

et al. 2019

Journal of Allergy and Clinical Immunology

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Caspase recruitment domain (CARD) protein-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] complexes are critical signaling adaptors that facilitate immune and inflammatory responses downstream of both cell surface and intracellular receptors. Germline mutations that alter the function of members of this complex (termed CBMopathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis. With an increasing number of patients being described in recent years, the clinical spectrum of diseases associated with CBM-opathies is rapidly expanding and becoming unexpectedly heterogeneous. Here we review major discoveries that have shaped our understanding of CBM complex biology, and we provide an overview of the clinical presentation, diagnostic approach, and treatment options for those carrying germline mutations affecting CARD9,

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Section: Discovery Of the Cbm Complexes And Germline Cbm-opathiesmentioning

confidence: 99%

Germline CBM-opathies: From immunodeficiency to atopy

Lu¹,

Biggs

Blanchard-Rohner

et al. 2019

Journal of Allergy and Clinical Immunology

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“…AD is considered to be caused by a combination of immunologic abnormalities and epidermal barrier defects. 1 Our previously reported cases of PRP type V showed fine, scaly, diffuse erythema on the face, trunk, and extremities, mimicking phenotypes of ichthyosis with skin barrier defects. 3,5 In the present patient, multiple eczematous lesions and laboratory data of AD (moderately elevated IgE and TARC) were observed.…”

mentioning

confidence: 86%

Aberrant CARD14 function might cause defective barrier formation

Murase

Takeichi

Akiyama

2019

Journal of Allergy and Clinical Immunology

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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.

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“…However, it is possible that metabolic derangement in other cellular compartments may also contribute to atopy. While CARD11 expression is largely restricted to the hematopoietic system, dominant negative mutations in CARD14 , a homolog largely restricted to keratinocytes, are also associated with atopic dermatitis . The function of CARD14 is analogous to the function of CARD11 in lymphocytes, comprising part of the CBM complex within the skin.…”

Section: When Atopy Is In the Card(s)mentioning

confidence: 99%

“…While CARD11 expression is largely restricted to the hematopoietic system, dominant negative mutations in CARD14, a homolog largely restricted to keratinocytes, are also associated with atopic dermatitis. 65 The function of CARD14 is analogous to the function of CARD11 in lymphocytes, comprising part of the CBM complex within the skin. While reported mutations have been associated with decreased antimicrobial peptide expression and diminished NF-κB activation, the potential effects of CARD14 mutations on mTOR and any role this might have on the immunopathogenesis of atopy has not been examined.…”

Section: When Atopy Is In the C Ard (S)mentioning

confidence: 99%

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

Lyons

Milner

2018

Immunological Reviews

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Summary Dynamic changes in metabolism have long been understood as critical for both the initiation and maintenance of innate and adaptive immune responses. A number of recent advances have clarified details of how metabolic pathways can specifically affect cellular function in immune cells. Critical to this understanding is ongoing study of the congenital disorders of glycosylation and other genetic disorders of metabolism that lead to altered immune function in humans. While there are a number of immune phenotypes associated with metabolic derangements caused by single gene disorders, several genetic mutations have begun to link discrete alterations in metabolism and growth specifically with allergic disease. This subset of primary atopic disorders is of particular interest as they illuminate how hypomorphic mutations which allow for some residual function of mutated protein products permit the “abnormal” allergic response. This review will highlight how mutations altering sugar metabolism and mTOR activation place similar constraints on T lymphocyte metabolism to engender atopy, and how alterations in JAK/STAT signaling can impair growth and cellular metabolism while concomitantly promoting allergic diseases and reactions in humans.

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Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis

Cited by 63 publications

References 65 publications

Germline CBM-opathies: From immunodeficiency to atopy

Germline CBM-opathies: From immunodeficiency to atopy

Aberrant CARD14 function might cause defective barrier formation

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

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