Association of Somatic <i>ATP2A2</i> Damaging Variants With Grover Disease

Seli, Devin; Ellis, Katharine T.; Goldust, Mohamad; Shah, Khadim; Hu, Ronghua; Zhou, Jing; McNiff, Jennifer M.; Choate, Keith A.

doi:10.1001/jamadermatol.2023.1139

Cited by 9 publications

(5 citation statements)

References 18 publications

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“…Moreover, while we have genetic studies recognizing specific mutations in the two forms of GGD, there is a notable absence of extensive genetic research on Grover's disease. Recent evidence show the presence of ATP2A2 mutations in Grover's disease [71], while mutations in the KRT5 gene, which are found in GGD, are rarely reported in GD [72]. This supports the idea that hereditary GGD is a distinct entity, while sporadic cases in adults may be part of the broader spectrum of GD.…”

Section: Diagnosis Of Galli-galli Diseasementioning

confidence: 53%

Galli–Galli Disease: A Comprehensive Literature Review

Michelerio,

Greco,

Tomasini

et al. 2024

Dermatopathology

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Galli–Galli disease (GGD) is a rare genodermatosis that exhibits autosomal dominant inheritance with variable penetrance. GGD typically manifests with erythematous macules, papules, and reticulate hyperpigmentation in flexural areas. A distinct atypical variant exists, which features brown macules predominantly on the trunk, lower limbs, and extremities, with a notable absence of the hallmark reticulated hyperpigmentation in flexural areas. This review includes a detailed literature search and examines cases since GGD’s first description in 1982. It aims to synthesize the current knowledge on GGD, covering its etiology, clinical presentation, histopathology, diagnosis, and treatment. A significant aspect of this review is the exploration of the genetic, histopathological, and clinical parallels between GGD and Dowling-Degos disease (DDD), which is another rare autosomal dominant genodermatosis, particularly focusing on their shared mutations in the KRT5 and POGLUT1 genes. This supports the hypothesis that GGD and DDD may be different phenotypic expressions of the same pathological condition, although they have traditionally been recognized as separate entities, with suprabasal acantholysis being a distinctive feature of GGD. Lastly, this review discusses the existing treatment approaches, underscoring the absence of established guidelines and the limited effectiveness of various treatments.

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Section: Diagnosis Of Galli-galli Diseasementioning

confidence: 53%

Galli–Galli Disease: A Comprehensive Literature Review

Michelerio,

Greco,

Tomasini

et al. 2024

Dermatopathology

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“…Similarly, transient acantholytic dermatosis (Grover disease), sharing clinical and histopathologic features with DD, manifests skin lesions during the sixth decade of life or later and, as the name suggests, they are transient in nature. Recently, somatic ATP2A2 variants have been identified in Grover disease skin lesions . Our findings are consistent with existing knowledge from mosaic DD and Grover disease, bolstering the concept that second hits may lead to more severe and persistent lesions, less responsive to therapy, whereas somatic heterozygosity in DD contributes to lesion transiency.…”

Section: Discussionmentioning

confidence: 99%

Persistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene

Atzmony,

Zagairy,

Mawassi

et al. 2024

JAMA Dermatol

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ImportanceDarier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinical manifestations include recurrent hyperkeratotic papules and plaques that occur mainly in seborrheic areas. Although some of the lesions wax and wane in response to environmental factors, others are severe and respond poorly to therapy.ObjectiveTo investigate the molecular mechanism underlying the persistency of skin lesions in DD.Design, Setting, and ParticipantsIn this case series, DNA was extracted from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was used using paired-whole exome sequencing of affected skin and blood or by deep sequencing of ATP2A2 of affected skin. Chromosomal microarray analysis was used to reveal copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism.Interventions or ExposuresPaired whole-exome sequencing and deep sequencing of ATP2A2 gene from blood and skin samples isolated from persistent, transient lesions and unaffected skin in patients with DD.Main Outcomes and MeasuresGermline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD.ResultsOf 9 patients with DD, all had heterozygous pathogenic germline variants in the ATP2A2 gene, 6 were female. Participant age ranged from 40 to 69 years on enrollment. All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene. The somatic variants were classified as highly deleterious via combined annotation-dependent depletion (CADD) scores or affect splicing, and 3 of them had been previously described in patients with DD and acrokeratosis verruciformis of Hopf. Second-hit variants in the ATP2A2 gene were not identified in the transient lesions (n = 2) or the normal skin (n = 2).Conclusions and RelevanceIn this study, persistent DD lesions were associated with the presence of second-hit somatic variants in the ATP2A2 gene. Identification of these second-hit variants offers valuable insight into the underlying mechanisms that contribute to the lasting nature of persistent DD lesions.

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“…Intriguingly, the pathologic features of GD can be identical to Darier disease (9,10,24), a genetic disorder linked to mutation of a calcium ATPase (SERCA2) embedded in the endoplasmic reticulum (11). Up to now, it remained unclear why these two disorders would exhibit such similar findings in biopsies that pathologists cannot consistently distinguish the diagnoses without additional clinical information, such as whether the eruption is known to be hereditary (Darier disease) or spontaneous (Grover disease).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the pathologic features of GD can be indistinguishable from a genetic blistering disorder called Darier disease (9,10), suggesting they may share a pathogenic mechanism. In fact, recent sequencing of GD lesions found acquired mutations in ATP2A2 (11), the gene linked to DD (12,13).…”

Section: Introductionmentioning

confidence: 99%

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

Simpson,

Tiwaa,

Zaver

et al. 2024

Preprint

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Grover disease is an acquired dermatologic disorder characterized by pruritic vesicular and eroded skin lesions. While its pathologic features are well-defined, including impaired cohesion of epidermal keratinocytes, the etiology of Grover disease remains unclear and it lacks any FDA-approved therapy. Interestingly, drug-induced Grover disease occurs in patients treated with B-RAF inhibitors that can paradoxically activate C-RAF and the downstream kinase MEK. We recently identified hyperactivation of MEK and ERK as key drivers of Darier disease, which is histologically identical to Grover disease, supporting our hypothesis that they share a pathogenic mechanism. To model drug-induced Grover disease, we treated human keratinocytes with clinically utilized B-RAF inhibitors dabrafenib or vemurafenib and leveraged a fluorescent biosensor to confirm they activated ERK, which disrupted intercellular junctions and compromised keratinocyte sheet integrity. Consistent with clinical data showing concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed excess ERK activity to rescue cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in skin biopsies of vemurafenib-induced Grover disease, but also in spontaneous Grover disease. In sum, our data define a pathogenic role for ERK hyperactivation in Grover disease and support MEK inhibition as a therapeutic strategy.

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Association of Somatic ATP2A2 Damaging Variants With Grover Disease

Cited by 9 publications

References 18 publications

Galli–Galli Disease: A Comprehensive Literature Review

Galli–Galli Disease: A Comprehensive Literature Review

Persistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

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